Chromatin organization refers to the composition and conformation of complexes between DNA, protein and RNA. It is determined by processes that result in the specification, formation or maintenance of the physical structure of eukaryotic chromatin. These processes include histone modification, DNA modification, and transcription. The modifications are bound by specific proteins that alter the conformation of chromatin.
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Raijmakers R, Zendman AJ, Egberts WV, Vossenaar ER, Raats J, Soede-Huijbregts C, Rutjes FP, van Veelen PA, Drijfhout JW, Pruijn GJ.; ''Methylation of arginine residues interferes with citrullination by peptidylarginine deiminases in vitro.''; PubMedEurope PMCScholia
Fodor BD, Kubicek S, Yonezawa M, O'Sullivan RJ, Sengupta R, Perez-Burgos L, Opravil S, Mechtler K, Schotta G, Jenuwein T.; ''Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells.''; PubMedEurope PMCScholia
Lee S, Lee DK, Dou Y, Lee J, Lee B, Kwak E, Kong YY, Lee SK, Roeder RG, Lee JW.; ''Coactivator as a target gene specificity determinant for histone H3 lysine 4 methyltransferases.''; PubMedEurope PMCScholia
Wysocka J, Myers MP, Laherty CD, Eisenman RN, Herr W.; ''Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1.''; PubMedEurope PMCScholia
Kuo AJ, Cheung P, Chen K, Zee BM, Kioi M, Lauring J, Xi Y, Park BH, Shi X, Garcia BA, Li W, Gozani O.; ''NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming.''; PubMedEurope PMCScholia
Pal S, Vishwanath SN, Erdjument-Bromage H, Tempst P, Sif S.; ''Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes.''; PubMedEurope PMCScholia
Huang H, Rambaldi I, Daniels E, Featherstone M.; ''Expression of the Wdr9 gene and protein products during mouse development.''; PubMedEurope PMCScholia
Bauer UM, Daujat S, Nielsen SJ, Nightingale K, Kouzarides T.; ''Methylation at arginine 17 of histone H3 is linked to gene activation.''; PubMedEurope PMCScholia
Tang J, Gary JD, Clarke S, Herschman HR.; ''PRMT 3, a type I protein arginine N-methyltransferase that differs from PRMT1 in its oligomerization, subcellular localization, substrate specificity, and regulation.''; PubMedEurope PMCScholia
Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G, Reinberg D, Jenuwein T.; ''A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin.''; PubMedEurope PMCScholia
Ma H, Baumann CT, Li H, Strahl BD, Rice R, Jelinek MA, Aswad DW, Allis CD, Hager GL, Stallcup MR.; ''Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter.''; PubMedEurope PMCScholia
Wilkins SE, Islam MS, Gannon JM, Markolovic S, Hopkinson RJ, Ge W, Schofield CJ, Chowdhury R.; ''JMJD5 is a human arginyl C-3 hydroxylase.''; PubMedEurope PMCScholia
Zhang Y, Iratni R, Erdjument-Bromage H, Tempst P, Reinberg D.; ''Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex.''; PubMedEurope PMCScholia
Friesen WJ, Wyce A, Paushkin S, Abel L, Rappsilber J, Mann M, Dreyfuss G.; ''A novel WD repeat protein component of the methylosome binds Sm proteins.''; PubMedEurope PMCScholia
Wang H, An W, Cao R, Xia L, Erdjument-Bromage H, Chatton B, Tempst P, Roeder RG, Zhang Y.; ''mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression.''; PubMedEurope PMCScholia
Horton JR, Upadhyay AK, Qi HH, Zhang X, Shi Y, Cheng X.; ''Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases.''; PubMedEurope PMCScholia
Hayashi K, Yoshida K, Matsui Y.; ''A histone H3 methyltransferase controls epigenetic events required for meiotic prophase.''; PubMedEurope PMCScholia
Qiao Q, Li Y, Chen Z, Wang M, Reinberg D, Xu RM.; ''The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation.''; PubMedEurope PMCScholia
Doyon Y, Cayrou C, Ullah M, Landry AJ, Côté V, Selleck W, Lane WS, Tan S, Yang XJ, Côté J.; ''ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation.''; PubMedEurope PMCScholia
Champagne KS, Saksouk N, Peña PV, Johnson K, Ullah M, Yang XJ, Côté J, Kutateladze TG.; ''The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide.''; PubMedEurope PMCScholia
Chin HG, Patnaik D, Estève PO, Jacobsen SE, Pradhan S.; ''Catalytic properties and kinetic mechanism of human recombinant Lys-9 histone H3 methyltransferase SUV39H1: participation of the chromodomain in enzymatic catalysis.''; PubMedEurope PMCScholia
Strahl BD, Briggs SD, Brame CJ, Caldwell JA, Koh SS, Ma H, Cook RG, Shabanowitz J, Hunt DF, Stallcup MR, Allis CD.; ''Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1.''; PubMedEurope PMCScholia
Chavanas S, Méchin MC, Takahara H, Kawada A, Nachat R, Serre G, Simon M.; ''Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6.''; PubMedEurope PMCScholia
Ciferri C, Lander GC, Maiolica A, Herzog F, Aebersold R, Nogales E.; ''Molecular architecture of human polycomb repressive complex 2.''; PubMedEurope PMCScholia
Lee N, Zhang J, Klose RJ, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y.; ''The trithorax-group protein Lid is a histone H3 trimethyl-Lys4 demethylase.''; PubMedEurope PMCScholia
Pinheiro I, Margueron R, Shukeir N, Eisold M, Fritzsch C, Richter FM, Mittler G, Genoud C, Goyama S, Kurokawa M, Son J, Reinberg D, Lachner M, Jenuwein T.; ''Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity.''; PubMedEurope PMCScholia
Brown MA, Sims RJ, Gottlieb PD, Tucker PW.; ''Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex.''; PubMedEurope PMCScholia
Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, Yagyu R, Nakamura Y.; ''SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells.''; PubMedEurope PMCScholia
Marks PA, Richon VM, Rifkind RA.; ''Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells.''; PubMedEurope PMCScholia
Liu F, Zhao X, Perna F, Wang L, Koppikar P, Abdel-Wahab O, Harr MW, Levine RL, Xu H, Tefferi A, Deblasio A, Hatlen M, Menendez S, Nimer SD.; ''JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation.''; PubMedEurope PMCScholia
Milne TA, Dou Y, Martin ME, Brock HW, Roeder RG, Hess JL.; ''MLL associates specifically with a subset of transcriptionally active target genes.''; PubMedEurope PMCScholia
Lu Y, Chang Q, Zhang Y, Beezhold K, Rojanasakul Y, Zhao H, Castranova V, Shi X, Chen F.; ''Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3.''; PubMedEurope PMCScholia
Hyllus D, Stein C, Schnabel K, Schiltz E, Imhof A, Dou Y, Hsieh J, Bauer UM.; ''PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation.''; PubMedEurope PMCScholia
Cai Y, Jin J, Swanson SK, Cole MD, Choi SH, Florens L, Washburn MP, Conaway JW, Conaway RC.; ''Subunit composition and substrate specificity of a MOF-containing histone acetyltransferase distinct from the male-specific lethal (MSL) complex.''; PubMedEurope PMCScholia
Ciccone DN, Su H, Hevi S, Gay F, Lei H, Bajko J, Xu G, Li E, Chen T.; ''KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints.''; PubMedEurope PMCScholia
Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, Roeder RG, Clarke S, Stallcup MR, Allis CD, Coonrod SA.; ''Human PAD4 regulates histone arginine methylation levels via demethylimination.''; PubMedEurope PMCScholia
Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument-Bromage H, Tempst P, Gilliland DG, Zhang Y, Kaelin WG.; ''The retinoblastoma binding protein RBP2 is an H3K4 demethylase.''; PubMedEurope PMCScholia
Demers C, Chaturvedi CP, Ranish JA, Juban G, Lai P, Morle F, Aebersold R, Dilworth FJ, Groudine M, Brand M.; ''Activator-mediated recruitment of the MLL2 methyltransferase complex to the beta-globin locus.''; PubMedEurope PMCScholia
Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D.; ''Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation.''; PubMedEurope PMCScholia
Hung T, Binda O, Champagne KS, Kuo AJ, Johnson K, Chang HY, Simon MD, Kutateladze TG, Gozani O.; ''ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation.''; PubMedEurope PMCScholia
Yin Y, Liu C, Tsai SN, Zhou B, Ngai SM, Zhu G.; ''SET8 recognizes the sequence RHRK20VLRDN within the N terminus of histone H4 and mono-methylates lysine 20.''; PubMedEurope PMCScholia
Verreault A, Kaufman PD, Kobayashi R, Stillman B.; ''Nucleosomal DNA regulates the core-histone-binding subunit of the human Hat1 acetyltransferase.''; PubMedEurope PMCScholia
Qi HH, Sarkissian M, Hu GQ, Wang Z, Bhattacharjee A, Gordon DB, Gonzales M, Lan F, Ongusaha PP, Huarte M, Yaghi NK, Lim H, Garcia BA, Brizuela L, Zhao K, Roberts TM, Shi Y.; ''Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development.''; PubMedEurope PMCScholia
Zhang Y, LeRoy G, Seelig HP, Lane WS, Reinberg D.; ''The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities.''; PubMedEurope PMCScholia
Aggarwal P, Vaites LP, Kim JK, Mellert H, Gurung B, Nakagawa H, Herlyn M, Hua X, Rustgi AK, McMahon SB, Diehl JA.; ''Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase.''; PubMedEurope PMCScholia
Schiltz RL, Mizzen CA, Vassilev A, Cook RG, Allis CD, Nakatani Y.; ''Overlapping but distinct patterns of histone acetylation by the human coactivators p300 and PCAF within nucleosomal substrates.''; PubMedEurope PMCScholia
Marks PA, Breslow R.; ''Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug.''; PubMedEurope PMCScholia
Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y.; ''Histone demethylation by a family of JmjC domain-containing proteins.''; PubMedEurope PMCScholia
Kanno T, Kawada A, Yamanouchi J, Yosida-Noro C, Yoshiki A, Shiraiwa M, Kusakabe M, Manabe M, Tezuka T, Takahara H.; ''Human peptidylarginine deiminase type III: molecular cloning and nucleotide sequence of the cDNA, properties of the recombinant enzyme, and immunohistochemical localization in human skin.''; PubMedEurope PMCScholia
Fleischer TC, Yun UJ, Ayer DE.; ''Identification and characterization of three new components of the mSin3A corepressor complex.''; PubMedEurope PMCScholia
Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H, Shinkai Y.; ''G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis.''; PubMedEurope PMCScholia
Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess JL.; ''MLL targets SET domain methyltransferase activity to Hox gene promoters.''; PubMedEurope PMCScholia
Levy D, Kuo AJ, Chang Y, Schaefer U, Kitson C, Cheung P, Espejo A, Zee BM, Liu CL, Tangsombatvisit S, Tennen RI, Kuo AY, Tanjing S, Cheung R, Chua KF, Utz PJ, Shi X, Prinjha RK, Lee K, Garcia BA, Bedford MT, Tarakhovsky A, Cheng X, Gozani O.; ''Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling.''; PubMedEurope PMCScholia
Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K.; ''PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex.''; PubMedEurope PMCScholia
Huang C, Xiang Y, Wang Y, Li X, Xu L, Zhu Z, Zhang T, Zhu Q, Zhang K, Jing N, Chen CD.; ''Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4.''; PubMedEurope PMCScholia
Fischer DD, Cai R, Bhatia U, Asselbergs FA, Song C, Terry R, Trogani N, Widmer R, Atadja P, Cohen D.; ''Isolation and characterization of a novel class II histone deacetylase, HDAC10.''; PubMedEurope PMCScholia
Alland L, David G, Shen-Li H, Potes J, Muhle R, Lee HC, Hou H, Chen K, DePinho RA.; ''Identification of mammalian Sds3 as an integral component of the Sin3/histone deacetylase corepressor complex.''; PubMedEurope PMCScholia
Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Müller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S.; ''Histone recognition and large-scale structural analysis of the human bromodomain family.''; PubMedEurope PMCScholia
Smith ER, Cayrou C, Huang R, Lane WS, Côté J, Lucchesi JC.; ''A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16.''; PubMedEurope PMCScholia
Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, Zhang Y.; ''Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain.''; PubMedEurope PMCScholia
Gilbert N, Gilchrist S, Bickmore WA.; ''Chromatin organization in the mammalian nucleus.''; PubMedEurope PMCScholia
Hakimi MA, Bochar DA, Chenoweth J, Lane WS, Mandel G, Shiekhattar R.; ''A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes.''; PubMedEurope PMCScholia
Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T.; ''Regulation of chromatin structure by site-specific histone H3 methyltransferases.''; PubMedEurope PMCScholia
Baba A, Ohtake F, Okuno Y, Yokota K, Okada M, Imai Y, Ni M, Meyer CA, Igarashi K, Kanno J, Brown M, Kato S.; ''PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B.''; PubMedEurope PMCScholia
Carapeti M, Aguiar RC, Goldman JM, Cross NC.; ''A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia.''; PubMedEurope PMCScholia
Kim SM, Kee HJ, Eom GH, Choe NW, Kim JY, Kim YS, Kim SK, Kook H, Kook H, Seo SB.; ''Characterization of a novel WHSC1-associated SET domain protein with H3K4 and H3K27 methyltransferase activity.''; PubMedEurope PMCScholia
Mandal M, Hamel KM, Maienschein-Cline M, Tanaka A, Teng G, Tuteja JH, Bunker JJ, Bahroos N, Eppig JJ, Schatz DG, Clark MR.; ''Histone reader BRWD1 targets and restricts recombination to the Igk locus.''; PubMedEurope PMCScholia
VanderMolen KM, McCulloch W, Pearce CJ, Oberlies NH.; ''Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma.''; PubMedEurope PMCScholia
Hu E, Chen Z, Fredrickson T, Zhu Y, Kirkpatrick R, Zhang GF, Johanson K, Sung CM, Liu R, Winkler J.; ''Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor.''; PubMedEurope PMCScholia
Migliori V, Müller J, Phalke S, Low D, Bezzi M, Mok WC, Sahu SK, Gunaratne J, Capasso P, Bassi C, Cecatiello V, De Marco A, Blackstock W, Kuznetsov V, Amati B, Mapelli M, Guccione E.; ''Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance.''; PubMedEurope PMCScholia
Kawasaki H, Schiltz L, Chiu R, Itakura K, Taira K, Nakatani Y, Yokoyama KK.; ''ATF-2 has intrinsic histone acetyltransferase activity which is modulated by phosphorylation.''; PubMedEurope PMCScholia
Hsia DA, Tepper CG, Pochampalli MR, Hsia EY, Izumiya C, Huerta SB, Wright ME, Chen HW, Kung HJ, Izumiya Y.; ''KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation.''; PubMedEurope PMCScholia
Andrés ME, Burger C, Peral-Rubio MJ, Battaglioli E, Anderson ME, Grimes J, Dallman J, Ballas N, Mandel G.; ''CoREST: a functional corepressor required for regulation of neural-specific gene expression.''; PubMedEurope PMCScholia
Schurter BT, Koh SS, Chen D, Bunick GJ, Harp JM, Hanson BL, Henschen-Edman A, Mackay DR, Stallcup MR, Aswad DW.; ''Methylation of histone H3 by coactivator-associated arginine methyltransferase 1.''; PubMedEurope PMCScholia
Kim JY, Kee HJ, Choe NW, Kim SM, Eom GH, Baek HJ, Kook H, Kook H, Seo SB.; ''Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity.''; PubMedEurope PMCScholia
Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, Shi Y.; ''Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases.''; PubMedEurope PMCScholia
Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J, Zhang Y.; ''JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor.''; PubMedEurope PMCScholia
Li G, Reinberg D.; ''Chromatin higher-order structures and gene regulation.''; PubMedEurope PMCScholia
Zhao Q, Rank G, Tan YT, Li H, Moritz RL, Simpson RJ, Cerruti L, Curtis DJ, Patel DJ, Allis CD, Cunningham JM, Jane SM.; ''PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing.''; PubMedEurope PMCScholia
Seward DJ, Cubberley G, Kim S, Schonewald M, Zhang L, Tripet B, Bentley DL.; ''Demethylation of trimethylated histone H3 Lys4 in vivo by JARID1 JmjC proteins.''; PubMedEurope PMCScholia
Chang B, Chen Y, Zhao Y, Bruick RK.; ''JMJD6 is a histone arginine demethylase.''; PubMedEurope PMCScholia
Ahringer J.; ''NuRD and SIN3 histone deacetylase complexes in development.''; PubMedEurope PMCScholia
O'Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P, Doorduijn J, Hess G, Jurczak W, Knoblauch P, Chawla S, Bhat G, Choi MR, Walewski J, Savage K, Foss F, Allen LF, Shustov A.; ''Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study.''; PubMedEurope PMCScholia
Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Antal T, Hansen KH, Helin K.; ''The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3.''; PubMedEurope PMCScholia
Liu W, Tanasa B, Tyurina OV, Zhou TY, Gassmann R, Liu WT, Ohgi KA, Benner C, Garcia-Bassets I, Aggarwal AK, Desai A, Dorrestein PC, Glass CK, Rosenfeld MG.; ''PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression.''; PubMedEurope PMCScholia
Cao R, Zhang Y.; ''SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex.''; PubMedEurope PMCScholia
Guccione E, Bassi C, Casadio F, Martinato F, Cesaroni M, Schuchlautz H, Lüscher B, Amati B.; ''Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive.''; PubMedEurope PMCScholia
Kim JY, Kim KB, Eom GH, Choe N, Kee HJ, Son HJ, Oh ST, Kim DW, Pak JH, Baek HJ, Kook H, Hahn Y, Kook H, Chakravarti D, Seo SB.; ''KDM3B is the H3K9 demethylase involved in transcriptional activation of lmo2 in leukemia.''; PubMedEurope PMCScholia
Marzluff WF, Gongidi P, Woods KR, Jin J, Maltais LJ.; ''The human and mouse replication-dependent histone genes.''; PubMedEurope PMCScholia
Guenther MG, Barak O, Lazar MA.; ''The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3.''; PubMedEurope PMCScholia
Lacroix M, El Messaoudi S, Rodier G, Le Cam A, Sardet C, Fabbrizio E.; ''The histone-binding protein COPR5 is required for nuclear functions of the protein arginine methyltransferase PRMT5.''; PubMedEurope PMCScholia
Loyola A, Almouzni G.; ''Marking histone H3 variants: how, when and why?''; PubMedEurope PMCScholia
Waldmann T, Izzo A, Kamieniarz K, Richter F, Vogler C, Sarg B, Lindner H, Young NL, Mittler G, Garcia BA, Schneider R.; ''Methylation of H2AR29 is a novel repressive PRMT6 target.''; PubMedEurope PMCScholia
Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee A, Biondi CA, Kay GF, Hayward NK, Hess JL, Meyerson M.; ''Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus.''; PubMedEurope PMCScholia
Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y.; ''Histone demethylation mediated by the nuclear amine oxidase homolog LSD1.''; PubMedEurope PMCScholia
Torres-Padilla ME, Parfitt DE, Kouzarides T, Zernicka-Goetz M.; ''Histone arginine methylation regulates pluripotency in the early mouse embryo.''; PubMedEurope PMCScholia
Mendjan S, Taipale M, Kind J, Holz H, Gebhardt P, Schelder M, Vermeulen M, Buscaino A, Duncan K, Mueller J, Wilm M, Stunnenberg HG, Saumweber H, Akhtar A.; ''Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila.''; PubMedEurope PMCScholia
Palacios A, Muñoz IG, Pantoja-Uceda D, Marcaida MJ, Torres D, Martín-García JM, Luque I, Montoya G, Blanco FJ.; ''Molecular basis of histone H3K4me3 recognition by ING4.''; PubMedEurope PMCScholia
Buggy JJ, Sideris ML, Mak P, Lorimer DD, McIntosh B, Clark JM.; ''Cloning and characterization of a novel human histone deacetylase, HDAC8.''; PubMedEurope PMCScholia
Loenarz C, Ge W, Coleman ML, Rose NR, Cooper CD, Klose RJ, Ratcliffe PJ, Schofield CJ.; ''PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilon-dimethyl lysine demethylase.''; PubMedEurope PMCScholia
Ueda H, Nakajima H, Hori Y, Fujita T, Nishimura M, Goto T, Okuhara M.; ''FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity.''; PubMedEurope PMCScholia
Xiao B, Jing C, Wilson JR, Walker PA, Vasisht N, Kelly G, Howell S, Taylor IA, Blackburn GM, Gamblin SJ.; ''Structure and catalytic mechanism of the human histone methyltransferase SET7/9.''; PubMedEurope PMCScholia
Eom GH, Kim KB, Kim JH, Kim JY, Kim JR, Kee HJ, Kim DW, Choe N, Park HJ, Son HJ, Choi SY, Kook H, Seo SB.; ''Histone methyltransferase SETD3 regulates muscle differentiation.''; PubMedEurope PMCScholia
Guerrin M, Ishigami A, Méchin MC, Nachat R, Valmary S, Sebbag M, Simon M, Senshu T, Serre G.; ''cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type I.''; PubMedEurope PMCScholia
Nakayama-Hamada M, Suzuki A, Kubota K, Takazawa T, Ohsaka M, Kawaida R, Ono M, Kasuya A, Furukawa H, Yamada R, Yamamoto K.; ''Comparison of enzymatic properties between hPADI2 and hPADI4.''; PubMedEurope PMCScholia
Tanaka Y, Katagiri Z, Kawahashi K, Kioussis D, Kitajima S.; ''Trithorax-group protein ASH1 methylates histone H3 lysine 36.''; PubMedEurope PMCScholia
Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE, Helin K.; ''UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.''; PubMedEurope PMCScholia
Rice JC, Briggs SD, Ueberheide B, Barber CM, Shabanowitz J, Hunt DF, Shinkai Y, Allis CD.; ''Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains.''; PubMedEurope PMCScholia
Wen H, Li J, Song T, Lu M, Kan PY, Lee MG, Sha B, Shi X.; ''Recognition of histone H3K4 trimethylation by the plant homeodomain of PHF2 modulates histone demethylation.''; PubMedEurope PMCScholia
Ishigami A, Ohsawa T, Asaga H, Akiyama K, Kuramoto M, Maruyama N.; ''Human peptidylarginine deiminase type II: molecular cloning, gene organization, and expression in human skin.''; PubMedEurope PMCScholia
Zhang Y, Sun ZW, Iratni R, Erdjument-Bromage H, Tempst P, Hampsey M, Reinberg D.; ''SAP30, a novel protein conserved between human and yeast, is a component of a histone deacetylase complex.''; PubMedEurope PMCScholia
Neal KC, Pannuti A, Smith ER, Lucchesi JC.; ''A new human member of the MYST family of histone acetyl transferases with high sequence similarity to Drosophila MOF.''; PubMedEurope PMCScholia
Sun XJ, Wei J, Wu XY, Hu M, Wang L, Wang HH, Zhang QH, Chen SJ, Huang QH, Chen Z.; ''Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase.''; PubMedEurope PMCScholia
Tachibana M, Ueda J, Fukuda M, Takeda N, Ohta T, Iwanari H, Sakihama T, Kodama T, Hamakubo T, Shinkai Y.; ''Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9.''; PubMedEurope PMCScholia
Foreman KW, Brown M, Park F, Emtage S, Harriss J, Das C, Zhu L, Crew A, Arnold L, Shaaban S, Tucker P.; ''Structural and functional profiling of the human histone methyltransferase SMYD3.''; PubMedEurope PMCScholia
Feng W, Yonezawa M, Ye J, Jenuwein T, Grummt I.; ''PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation.''; PubMedEurope PMCScholia
Li Y, Trojer P, Xu CF, Cheung P, Kuo A, Drury WJ, Qiao Q, Neubert TA, Xu RM, Gozani O, Reinberg D.; ''The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate.''; PubMedEurope PMCScholia
Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ.; ''SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins.''; PubMedEurope PMCScholia
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Histones H3.1 and H3.2 are upregulated during DNA replication and are present in newly replicated chromatin. Histone H3.3 is synthesized throughout the cell cycle and is inserted post-replication.
Histones H3.1 and H3.2 are upregulated during DNA replication and are present in newly replicated chromatin. Histone H3.3 is synthesized throughout the cell cycle and is inserted post-replication.
Histones H3.1 and H3.2 are upregulated during DNA replication and are present in newly replicated chromatin. Histone H3.3 is synthesized throughout the cell cycle and is inserted post-replication.
Histones H3.1 and H3.2 are upregulated during DNA replication and are present in newly replicated chromatin. Histone H3.3 is synthesized throughout the cell cycle and is inserted post-replication.
Methylation of histones by protein arginine methyltransferases (PRMTs), in general, is required for mammalian development and plays an important and dynamic role in gene regulation. Protein-arginine deiminases (PADIs) catalyse the deimination of L-arginine residues (L-Arg) in proteins to L-citrulline (L-Cit), thus playing a role in the regulation of development (Guerrin et al. 2003, Ishigami et al. 2002, Kanno et al. 2000, Wang et al. 2004, Nakayama-Hamada et al. 2005, Chavanas et al. 2004).
Histone demethylases (HDMs) belong to two groups with distinct catalytic mechanisms. KDM1A and KDM1B (formerly known as Lysine Specific Demethylases 1 and 2), belong to the flavin adenine dinucleotide (FAD)-dependent amino oxidase family, releasing formaldehyde. The reaction mechanism requires a protonatable lysine epsilon-amino group, not available in trimethylated lysines (Shi et al. 2004). KDM1A and subsequently KDM1B were shown to catalyse demethylation of monomethyl and dimethyl, but not trimethyl, histone H3 at lysine 5 (H3K4) in vitro (Shi et al. 2004, Ciccone et al. 2009). Subsequently KDM1A was found to be much more proficient at catalysing demethylation of H3K4 when part of a multiprotein complex (Lee et al. 2005) and shown to catalyse demethylation of histone H3 at lysine 10 (H3K9) in vivo when associated with the androgen receptor (Metzger et al. 2007), suggesting that its substrate specificity is modulated by interacting proteins. KDM1A is a subunit of several complexes, including CtBP, Co-REST, NRD and BRAF35 (Lan et al. 2008). It is also able to catalyse demethylation of a number of non-histone proteins (Nicholson & Chen 2009).
Phosphorylation of WDR77 (MEP50) on threonine-5 by cyclin-dependent kinase 4 (CDK4), as part of the complex cyclin D1: CDK4:PRMT5:WDR77 enhances PRMT5:WDR77 methyltransferase activity, which triggers events associated with cyclin D1-dependent neoplastic growth (Aggarwal et al. 2011). Cyclin D1 is an allosteric regulator of CDK4 and CDK6, mediating growth factor-dependent G1-phase progression. Growth factor stimulation induces cyclin D1 expression, its association with CDK4 and nuclear accumulation during mid-G1. Active cyclin D1:CDK4 catalyzes the phosphorylation-dependent inactivation of retinoblastoma (RB) family proteins (Diehl 2002, Gladden & Diehl 2005). Following the G1/S transition, cyclin D1 accumulation is opposed by phosphorylation of threonine-286 (T286) by glycogen synthase kinase 3 beta (GSK3beta), which promotes cyclin D1 nuclear export (Alt et al. 2000).
Tyrosine phosphorylation of PRMT5 can block WDR77 (MEP50) binding, which attenuates PRMT5 activity (Liu et al. 2011). The kinase JAK2 is constitutively activated by the mutation V617F, observed in most patients with non-chronic myelogenous leukemia (nCML) myeloproliferative neoplasms (MPNs) (Liu et al. 2011). JAK2 V617F can phosphorylate STAT5 in the absence of upstream signals, which confers cytokine-independent growth to Ba/F3 cells and induces a myeloproliferative disease in mouse models (Akada et al. 2010, Marty et al., 2010, Mullally et al. 2010). JAK2 V617F phosphorylates PRMT5 predominantly at tyrosines 297, 304, and 307, significantly reducing the activity-enhancing interaction between PRMT5 and WDR77 (MEP50) (Liu et al. 2011).
In mammalian cells, PRMT5 is tightly bound by WDR77 (MEP50). This interaction is required for PRMT5 activity (Friesen et al. 2002). The structure of PRMT5 and WDR77 (MEP50) was determined, bound to an S-adenosylmethionine analog and a peptide substrate derived from histone H4. The structure reveals a hetero-octameric complex formation, with close interaction between the seven-bladed beta-propeller WDR77 (MEP50) and the N-terminal domain of human PRMT5 (Antonysamy et al. 2012, Ho et al. 2013)
The histone-binding protein cooperator of PRMT5 (COPRS) guides PRMT5:WDR77 to methylate histone H4 arginine-4 (H4R3) rather than histone H3 arginine-9 (H3R8) (Lacroix et al. 2008).
The hSWI/SNF chromatin remodelling complex can be found in association with PRMT5:WDR77, enhancing its methyltransferase activity towards histone substrates. Histone H3 arginine-9 (H3R8) and histone H4 arginine-4 (H4R3) are the preferred methylation sites of hSWI/SNF-associated PRMT5 (Pal et al. 2004).
SWI/SNF complexes are a family of ATP-dependent chromatin remodelling complexes involved in the activation and repression of gene transcription. They generate nucleosomes with altered positions, nucleosomes with DNA loops and nucleosomes that are capable of exchanging histone dimers or octamers (Racki & Narlikar 2008).
The core of the hSWI/SNF complex contains SMARCA4 (BRG1/BAF190A) or SMARCA2 (hBrm/BAF190B), SMARCC1 (BAF155), SMARCC2 (BAF170) and SMARCB1 (INI1) plus a variable number of additional subunits (Wang et al. 1996, Phelan et al. 1999, Reisman et al. 2009). SMARCA4 or SMARCA2 are the catalytic ATPase subunits. SMARCC1 and SMARCC2 are 62% identical to each other at the protein level (Wang et al. 1996). Loss of the SMARCB1 subunit (SWI/SNF-related matrix associated actin dependent regulator of chromatin B1) is a recurrent genetic characteristic of malignant rhabdoid tumor (MRT), a rare and aggressive pediatric cancer (Versteege et al. 1998, Biegel et al.1999). SMARCB1 mouse knockouts cause early embryonic lethality; heterozygous loss predisposes mice to MRT-like tumors (Klochendler-Yeivin et al. 2000, Roberts et al. 2000, Guidi et al. 2001). Actin and actin-related proteins found in hSWI/SNF complexes and are believed to facilitate nuclear matrix association (Zhao et al. 1998, Rando et al. 2002).
Peptidyl arginine deiminase (PADI) 4, PADI2 and PADI3 are able to convert peptidyl arginine to peptidyl citrulline. The guanidino group of arginine is hydrolyzed, yielding a ureido group and ammonia. This deimination (citrullination) mechanism is proposed as an alternative pathway for the reversal of arginine methylation (Cuthbert et al. 2004, Wang et al. 2004), whereby the methyl group was removed from a monomethylarginine residue by conversion of the residue to citrulline, releasing methylamine instead of ammonia. PADI4 was reported to specifically deiminate methylated arginine residues 3, 9, 18, and 27 in Histone H3, preventing arginine methylation by CARM1 (Cuthbert et al. 2004). Deimination may stabilize interactions between Histone H2A and H2B (Shimoyama et al. 2010).
Dysregulation of PADI activity is associated with a range of diseases, including rheumatoid arthritis (RA), multiple sclerosis, ulcerative colitis, neural degeneration, COPD, and cancer (Lange et al. 2011, McElwee et al. 2012).
KAT2A (GCN5) and KAT2B (PCAF) are histone acetyltransferases (HATs) that act as part of large multimember complexes to facilitate transcription by acetylating histones H3 and H4. In eukaryotes the SPT-ADA-GCN5 acetyltransferase (SAGA) complex has 19 subunits including TRRAP, ENY2, USP22 and subunits belonging to the ADA, SPT, TAF, and SGF group of proteins (Nagy et al. 2009). The ADA2A-containing (ATAC) complex shares with SAGA a core composed of KAT2A-TADA3 (ADA3)-CCDC101 (STAF36, SGF29) and either TADA2A (ADA2a) in ATAC, or TADA2B (ADA2b) in SAGA. ATAC complexes contain a second putative HAT, called CSRP2BP (ATAC2), and five other subunits; YEATS2, ZZZ3, MBIP, WDR5, and DR1 (NC2-Beta) (Guelman et al. 2009). CSRP2BP has weak HAT activity in vitro but it's main function is to maintain the structural integrity of ATAC (Guelman et al. 2009). At present, the biological function of the ATAC complex is not well understood. In vitro GCN5 acetylates mainly histone H3K14 (lysine-15 in the UniProt peptide which retains the initiating methionine), but when incorporated into the SAGA complex GCN5 becomes more efficient as an H3K14 acetylase and can also acetylate H3K9 and H3K18 (Brand et al. 1999, Grant et al. 1999), H3K23, and H3K27 (Kuo et al. 1996, Kuo & Andrews 2013). Drosophila ATAC mainly acetylates histone H4 (Ciurciu et al. 2006, Suganuma et al. 2008), suggested to be due to the presence of CSRP2BP in the complex (Suganuma et al. 2008) but different human ATAC preparations have exhibited a range of specificities with no clear difference between SAGA and ATAC (Guelman et al. 2009, Wang et al. 2008, Nagy et al. 2010). SAGA and ATAC complexes from mouse and human contain either GCN5 or PCAF in a mutually exclusive manner (Nagy et al. 2010, Krebs et al. 2010, Spedale et al. 2012).
The SAGA complex consists of KAT2A (hGCN5), TADA1 (STAF42), TADA2B (ADA2b), TADA3 (STAF54, ADA3), SUPT3H (SPT3), SUPT7L (STAF65G), TAF5L (PAF65B), TAF6L (PAF65A), TAF9 (TAFII31), TAF12 (TAFII20), TAF10 (TAFII31), TRRAP, SAP130 (Martinez et al. 2001), CCDC101, ATXN7, a factor termed STAF55 that cannot be identified, two further factors described as probable members that cannot be identified STAF46 and STAF60 (Nagy & Tora 2007) plus ATXN7L3, USP22, ENY2 (Zhao et al. 2008) and SUPT20H (Nagy et al. 2009).
N.B. Coordinates of post-translational modifications described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
Elongator Protein 3 (ELP3, KAT9) is the catalytic subunit of the highly conserved Elongator complex (Winkler et al. 2001, Hawkes et al. 2002, Li et al. 2005). This unstable six-subunit complex consists of two discrete three-subunit subcomplexes (Winkler et al. 2001). The core Elongator complex (Otero et al. 1999) contains IKBKAP, ELP2 and ELP3. ELP3 has motifs characteristic of the GCN5-related GNAT family of histone acetyltransferases (HATs), but the core Elongator complex has no intrinsic HAT activity, requiring the presence of a complex of Elp4, Elp5, and Elp6 proteins (Winkler et al. 2001).
The Elongator complex is directed specifically toward the N-terminal tails of histones H3 and H4, favouring acetylation at lysine-14 (K14) of histone H3 and lysine-8 (K8) of histone H4 (Winkler et al. 2002).
Yeast Elp3 nulls exhibit slow activation of certain genes and defects in histone H3 acetylation patterns essential for gene activation (Kristjuhan et al. 2002, Winkler et al. 2002, Kristjuhan & Svejstrup 2004). Elp3 is essential for the association of Elongator with nascent RNA in vivo (Petrakis et al. 2004; Svejstrup 2007).
Misregulation of ELP3 is implicated in human disorders that affect neuronal function, including familial dysautonomia (FD), an autosomal recessive neurodevelopmental disease characterized by degeneration of the sensory and autonomic nervous system (Slaugenhaupt & Gusella 2002, Simpson et al. 2009), and the motor neuron degenerative disorder amyotrophic lateral sclerosis (ALS) (Wallis et al. 2008). In mammalian cells Elp3 is essential for promoting transcription-activating histone H3 acetylation in the coding regions of certain neuronal cell motility genes (Close et al. 2006).
The Inhibitor of Growth (ING) family are growth regulators, present in all eukaryotes, with five human proteins ING1 to ING5. ING genes are mutated or downregulated in many forms of cancer. They have roles in chromatin modification and remodeling, gene-specific transcription regulation, and DNA repair, recombination, and replication (Saksouk et al. 2008, Awakumovv et al. 2012).
Human INGs can be divided into three groups: ING1/2, ING3, and ING4/5, based on their association with three distinct types of protein complexes (Doyon et al. 2006). All regulate chromatin via histone acetylation and deacetylation. The catalytic histone acetyltransferase (HAT) subunits of ING complexes are members of the MYST family, KAT5 (Tip60), KAT7 (HBO1) KAT6A (MOZ), KAT6B (MORF), and KAT8 (MOF). ING4 exists in vivo as a dimer, binding two lysine-4 trimethylated histone H3 (H3K4me3) modifications (Palacios et al. 2010). Homology modeling suggests that other INGs are likely to be dimers (Culurgioni et al. 2012).
KAT7-ING4/5 complexes interact with lysine-4 trimethylated histone H3 (H3K4me3), acetylating surrounding histone tails to stimulate local transcription (Palacios et al. 2008, Champagne et al. 2008, Hung et al. 2009, Saksouk et al. 2009).
ATF2 (activating transcription factor 2) is a basic leucine zipper (bZIP) protein and member of the activator protein-1 (AP-1) family (Wagner et al. 2001). The basic region of ATF2 binds DNA while the leucine zipper region allows dimerization with partners. ATF2 is a histone acetyltransferase (HAT), which specifically acetylates histones H2B and H4 in vitro. ATF2 is sequentially phosphorylated on threonine residues T69 and T71 by protein kinases ERK1/2 and p38 (van Dam et al. 1995, Livingstone et al. 1995, Ouwens et al. 2002, Baan et al. 2009). This phosphorylated form has increased HAT activity (Kawasaki et al. 2000).
KAT6A (Monocytic leukemia zinc finger protein, MOZ) and KAT6B (Monocytic leukemia zinc finger protein-related factor, MORF) are member of the MYST family of histone acetyltransferases, named after the founding members MOZ, Ybf2/Sas3, Sas2 and TIP60 (Borrow et al. 1996, Reifsnyder et al. 1996). The presence of a MYST domain is the only common structural motif in this family. MOZ and MORF are highly homologous (overall amino-acid sequence identity, 60%; similarity, 66%) but distinct from other family members (Yang & Ullah 2007).
KAT6A and KAT6B have intrinsic histone acetyltransferase activity (Champagne et al. 1999, 2001). Both can form tetrameric 'ING5' complexes with BRPF1 (possibly BRPF2 and 3), EAF6 and ING5. BRPF1 and EAF6 drastically stimulate the acetyltransferase activities of KAT6A/B against nucleosomal histone H3 (Doyon et al. 2006, Ullah et al. 2008). ING5-MOZ/MORF complexes acetylate only histone H3 at lysine-14.
KAT6A homozygous mice die at birth, with reduced hematopoiesis and profound defects in the stem cell compartment. These mice have no long-term repopulating stem cells and display substantial reduction in the number of multipotent cells able to form spleen colonies (Thomas et al. 2006). Chromosomal rearrangements of the KAT6A gene are associated with acute myeloid leukemia (AML), uterine leiomyomata and therapy-related myelodysplastic syndromes (Yang & Ullah, 2007).
Mutations in KAT6B are the cause of the Say-Barber-Biesecker variant of Ohdo syndrome and Genitopatellar syndrome (Campeau et al. 2012, Szakszon et al. 2013).
KAT8 (MOF, MYST1) is a member of the MYST (Moz-Ybf2/Sas3-Sas2-Tip60) family of histone acetyltransferases (HATs). KAT8 is the catalytic component of the nine-subunit non-specific lethal (NSL) complex (Mendjan et al. 2006, Cai et al. 2010).
NSL acetylates histone H4 on lysines 17 (H4K16), 6 (H4K5) and 9 (H4K8) (Cai et al. 2010).
KAT8 is also the catalytic subunit of the male-specific lethal (MSL) complex, which acetylates almost exclusively H4K16 and is responsible for a large fraction of H4K16 acetylation in human cells (Smith et al. 2005).
N.B. Coordinates of post-translational modifications described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
The MSL complex has histone acetyltransferase (HAT) activity with a high specificity for histone H4 lysine-17 (H4K16) (Smith et al. 2000, 2005, Conrad et al. 2012). The subunit responsible for this activity is KAT8 (Males Absent on the First, MOF) a member of the MYST (named for yeast and human members MOZ, YBF2, SAS2, and Tip60) HAT family. In Drosophilla, the MSL complex associates at hundreds of sites along the X chromosome in somatic cells, resulting in the hyperacetylation of H4K16 (Lavender et al. 1994, Smith et al. 2000). In humans MSL is responsible for the majority of H4 acetylation at lysine-17 in the cell. KAT8 is a component of other complexes (Smith et al. 2005, Mendjan et al. 2006, Cai et al. 2010).
The NuA4 complex contains the histone acetyltransferase (HAT) KAT5 (TIP60), a member of the MYST family. The first characterisation of a mammalian NuA4 complex identified the additonal components TRRAP, the Enhancer of Polycomb protein (EPC1), actin-like protein ACTL6A (BAF53a), which is a homolog of yeast Arp4, actin (ACTB), the SNF2-related helicase p400 (EP400) and the AAA ATPases RUVBL1 (TIP49a) and RUVBL2 (TIP49b) (Ikura et al. 2000). Subsequently further copmponents were identified as MRGBP, MORF4L1 (MRG15), MORF4L2 (MRGX), (Cai et al. 2003), BRD8, DMAP1, ING3, MEAF6, YEATS4 (Doyon et al. 2004) and VPS72 (YL1) (Cai et al. 2005).
In humans, newly synthesized histone H4 is acetylated by the cytoplasmic Type B histone acetyltransferase (HAT) complex, which is composed of RBBP7 and HAT1. This interacts with histones H4 and H2A, acetylating soluble but not nucleosomal histone H4 at lysine-6 (H4K5) and lysine-13 (H4K12) and to a lesser extent lysine-6 of histone H2A (H2AK5) (Verreault et al. 1996). The HAT1:RBBP7 complex is part of the sNASP complex, a chaperone for H3-H4 (Campos et al. 2010). HAT1 also has a role in homologous recombination repair, probably as part of a larger complex, facilitating the enrichment of H4K5/K12-acetylated H3.3 to double-strand breaks thereby marking the damaged area for subsequent recruitment of key repair factors (Yang et al. 2013).
N.B. Coordinates of post-translational modifications described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
EP300 and the related CREBBP are transcriptional regulators that interact with many other proteins. They have overlapping functions but also unique properties, particularly in vivo (Kalkhoven 2004). CREBBP and EP300 proteins are able to form a physical bridge between DNA-binding transcription factors and the RNA polymerase II complex. Histones are believed to be their main acetylation targets, but their ability to acetylate and thereby regulate transcription factors such as p53 (Gu & Roeder 1997) is also believed to be crucial (Kasper et al. 2006). EP300 can acetylate lysine-6 of histone H2A (H2AK5), lysines-12 (H2BK11), 15 (H2BK14) and to a lesser extent 5 and 20 of histone H2B, but preferentially acetylates lysines 14 and 18 of histone H3 and lysines 5 and 8 of histone H4 (Ogryzko et al. 1996, Schiltz et al. 1999). Heterozygous knockout of Ep300 is embryonic-lethal (Yao et al. 1998). Conditional knockouts have a phenotype that overlaps with that of conditional CREBBP knockouts (Kasper et al. 2006).
CREBBP (CBP) is named after its interaction with the CRE-binding protein CREB, though it interacts with many other proteins. It is thought to act as an integrator of signals from various pathways (Goodman & Smolik 2000), which compete for a limited amount of nuclear CREBBP. CREBBP and EP300 (p300) are closely related and have overlapping functions but also unique properties, particularly in vivo (Kalkhoven 2004). Both proteins form a physical bridge between DNA-binding transcription factors and the RNA polymerase II complex. Histones are believed to be the main acetylation targets of CREBBP and EP300, but their ability to acetylate and thereby regulate transcription factors such as p53 (Gu & Roeder 1997) is considered significant additional function (Kasper et al. 2006).
CREBBP has intrinsic histone acetyltransferase (HAT) activity on lysine-13 of H2B, lysine-15 of H3 and lysine-9 of H4 (Bannister & Kouzarides 1996, Rekowski & Giannis 2010, Barrett et al. 2011).
Homozygous knockout of CREBBP results in embryonic lethality (Tanaka et al. 1997). Focal deletion of CREBBP demonstrates that it is critical for the in vivo acetylation of lysines on histones H2B, H3 and H4, and cannot be compensated for by the p300 (Barrett et al. 2011).
Genomic aberrations in CREBBP are associated with Rubinstein-Taybi syndrome (Torress et al. 2013).
N.B. Coordinates of post-translational modifications described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
CLOCK is a central element of the core clock mechanism that governs circadian rhythms. It has intrinsic histone acetyltransferase (HAT) activity which regulates the transcription of many clock-controlled genes (Doi et al. 2006, Hirayama et al. 2007). The carboxy-terminal region of CLOCK displays significant sequence homology with the carboxy-terminal domain of NCOA3 (ACTR), which also has intrinsic HAT activity (Chen et al. 1997). CLOCK acetylates histones H3 and H4 with greatest activity at H3K14, lesser activity at H3K9, but does not acetylate H2A and H2B (Doi et al. 2006 and Nakahata et al. 2007).
HDAC1 and HDAC2 interact to form the catalytic core of several multisubunit complexes including the Sin3, nucleosome remodeling deacetylase (NuRD) and corepressor of REST (CoREST) complexes (Grozinger & Schreiber 2002). A 'core complex' of HDAC1/2 and the histone binding proteins RBBP7 (RbAp46) and RBBP4 (RbAp48), has been described in vivo and in vitro (Zhang et al. 1999). The Sin3 complex consists of this core complex plus SAP18 and SAP30, which appear to aid in stabilizing the protein associations and Sin3A, which serves as a scaffold for assembly of the complex and its interaction with various DNA binding proteins (Ayer 1999). Mammals express two Sin3 proteins, Sin3A and Sin3B. The recognized Sin3A core complex contains the HDAC1-2 catalytic core, SAP18 (Zhang et al. 1997), SAP30 (Zhang et al. 1998), RBBP7/4 (Ahringer 2000), SUDS3 (SAP45, SDS3) (Alland et al. 2002), ARID4B (SAP180) and SAP130 (Fleischer et al. 2003). Additional members are BRMS1 (breast cancer metastasis suppressor 1), ARID4A (Rb-binding protein 1) (Meehan et al. 2004) and SAP30L (Viiri et al. 2006). The Sin3A complex preferentially binds to hypoacetylated histones through the RBBP7/4 subunits (Vermeulen et al. 2004, Yoon et al. 2005). It can also be recruited to chromatin through the H3K4-di/trimethyl mark by ING1/2 (Shi et al. 2006, Pena et al. 2008).
The Sin3B complex shares some subunits in common with the Sin3A complex but may also contain distinct subunits (Le Guezennec et al. 2006a).
The NuRD complex contains a core histone deacetylase complex that consists of the HDAC1-2 catalytic core plus RBBP7 (RbAp46) and RBBP4 (RbAp48) (Ahringer 2000). The largest and key component is the Mi-2 remodelling subunit (dermatomyositis-specific autoantigen), which contains the ATPase/chromatin remodelling activity and physically associates with the other components. Mammals have two Mi-2 proteins: CHD3 (Mi-2alpha), and CHD4 (Mi-2 beta) (Seelig et al. 1996). CHD4 (Mi-2 beta) is the form predominantly associated with the NuRD complex (Zhang et al. 1998, Feng & Zhang 2001), although CHD3 is a member of the NuRD complex in a variety of human cell lines (Le Guezennec et al. 2006b). It is not clear whether functional differences exist between CHD3 and CHD4-containing complexes (McDonel et al. 2009). Further components are MBD3 (methyl CpG-binding domain 3), and a metastasis-associated (MTA) protein subunit. MTA subunits (e.g. Mta1, Mta2 or Mta3) appear to be mutually exclusive, possibly contributing to functional diversity of NuRD complexes (Bowen et al. 2004, Fujita et al. 2004). GATAD2A and GATAD2B proteins (formerly known as p66alpha and p66beta) are often reported as members of NuRD. MBD3 can be replaced by related protein MBD2, forming the MeCP1 complex (Feng & Zhang 2001, Le Guezennec et al. 2006b). The MeCP1 complex represents only a small proportion of the total NuRD complex in mammalian cells (Refs. in McDonel et al. 2009); MBD2 has been shown to be dispensable for normal mammalian development (Hendrich et al. 2001).
NuRD is recruited via MDB3 for DNA methylation-dependent gene silencing. It associates with MeCP1 (methyl CpG-binding protein 1) and MeCP2 to provide an intimate connection with DNA methylation (Denslow & Wade 2007, Klose & Bird 2006).
The CoREST complex minimally contains the HDAC1-2 catalytic core, REST (RE1-silencing transcription factor), RCOR1 (CoREST, KIAA0071) and KDM1A (BHC110, LSD1) (Andres et al. 1999, Humphrey et al. 2001). The BRAF–HDAC (BHC) complex consists of HDAC1-2, RCOR1, KDM1A, HMG20B (BRAF35) and PHF21A (BHC80) (Hakimi et al. 2002, Yang & Seto 2008).
This reaction represents a theoretical complete deacetylation of histone.
HDAC3 mediates the gene silencing activity of Retinoic acid and thyroid hormone receptor (SMRT) complex or the homologous nuclear receptor corepressor (NCoR). These coregulators are involved in a wide range of developmental and homeostatic processes, including metabolism, inflammation, and circadian rhythms (Mottis et al. 2013). HDAC3 interacts with a conserved SANT-like domain known as the deacetylase activating domain (DAD) within NCOR2 (SMRT) or NCOR1 (Li et al. 2000, Wen et al. 2000, Zhang et al. 2002, Yoon et al. 2003, Oberoi et al. 2011). This interaction both recruits and activates HDAC3 (Wen et al. 2000, Guenther et al. 2001, Zhang et al. 2002). Recruitment of HDAC3 to the DAD is essential for repression by the nuclear thyroid hormone receptor and for the maintenance of normal circadian physiology (You et al. 2010, Yin et al. 2007). A second SANT-like domain has been reported to interact directly with histone tails and termed the histone interaction domain (HID) (Hartman et al. 2005, Yu et al. 2003). NCORs are largely unstructured platform proteins that act as a scaffold upon which the enzymatic machinery of the repression complex is built (Watson et al. 2012). They can recruit other deacetylases such as HDAC4 (Fischle et al. 2002), HDAC5, HDAC7 (Kao et al. 2000), Sirt1 (Picard et al. 2004), and via mSin3, HDAC1 (Heinzel et al. 1997, Nagy et al. 1997). The importance of these deacetylase enzymes is not yet established. It has been demonstrated HDAC3 was shown to be responsible for deacetylase activities associated with HDAC4 and HDAC7 (Fischle et al. 2002). Corepressor complexes are heterogeneous, context-specific and transient in nature, but in addition to HDAC3, some additional partners are regularly found in stoichiometric association with NCOR1/NCOR2 and are essential for repressive function. These partners include the G protein pathway suppressor (GPS2) and transducing beta-like 1 (TBL1) and its homologue, TBL-related 1 (TBLR1), which together form the core repression complex (Oberoi et al. 2011). Ins(1,4,5,6)P4 is a further component of the complex (Watson et al. 2012).
HDAC8 can catalyze the in vitro deacetylation of a number of acetylated histone variants including full-length H2A/H2B, H3, and H4 histones acetylated at nonspecific lysines (Hu et al. 2000, Buggy et al. 2000). Peptide sequences corresponding to the H4 histone tail with an acetylated lysine at position sixteen (AcK16) were also identified as in vitro substrates (Buggy et al. 2000, Van der Wyngaert et al. 2000). Subsequent studies have used the H4 histone tail sequence as a peptide template to investigate the amino acid sequence preference of HDAC8. HDAC8 can catalyze the in vitro deacetylation of AcK20 on the H4 histone tail though at a much slower rate than deacetylation of AcK16 peptides (Dose et al. 2011). HDAC8 can catalyze deacetylation in vivo in the absence of a protein complex (Dowling et al. 2010). The role of HDAC8 in catalyzing deacetylation of specific sites in histones in vivo remains unclear (Wolfson et al. 2013).
HDAC10 is a class IIb HDAC subfamily member with greatest sequence similarity to HDAC6. Unlike HDAC6, HDAC10 is found in the nucleus. It is able to deacetylate acetylated histone H4 N-terminal peptides (Fischer et al. 2002, Guardiola & Yao 2002, Kao et al. 2002, Tong et al. 2002).
All characterised lysine demethylases other than KDM1A belong to the jumonji C-domain (JmjC) containing family, members of the Cupin superfamily of mononuclear Fe (II)-dependent oxygenases. They require 2-oxoglutarate (2-OG) and molecular oxygen as co-substrates, producing succinate and carbon dioxide. This hydroxylation-based mechanism does not require a protonatable lysine epsilon-amine group and consequently JmjC-containing demethylases are able to demethylate tri-, di- and monomethylated lyines.
The first reported JmjC-containing demethylases were KDM2A and KDM2B (JHDM1A/B, FBXL11/10). These demethylate lysine-37 of histone H3 when mono- or di-methylated (H3K36Me1/2) (Tsukada et al. 2006). KDM4A (JHDM3A) can demethylate mono-, di and trimethylated lysine-37 of histone H3 (Klose et al. 2006). KDM8 can demethylate diimethylated lysine-37 of histone H3 (Hsia et al. 2010).
All characterized lysine demethylases other than KDM1A belong to the jumonjiC domain (JmjC) containing family.The JmjC KDMs are members of the Cupin superfamily of mononuclear Fe (II) dependent oxygenases, which are characterized by the presence of a double-stranded beta-helix core fold. The JmjC KDMs require 2 oxoglutarate (2 OG) and molecular oxygen as co substrates, producing, along with formaldehyde, succinate and carbon dioxide. This hydroxylation based mechanism does not require a protonatable lysine e amine group and consequently JmjC containing demethylases are able to demethylate tri , di and monomethylated lysines. KDM4A-D (JMJD2A-D/JHDM3A-D) catalyse the demethylation of di- or tri-methylated histone H3 at lysine-10 (H3K9Me2/3) (Cloos et al. 2006, Fodor et al. 2006, Whetstine et al. 2007), with a strong preference for Me3 (Whetstine et al. 2007). MINA, a bifunctional histone lysine demethylase and ribosomal histidine hydroxylase, demethylates trimethylated lysine-10 of histone H3 (Lu et al. 2009).
KDM4A (JHDM3A) can also demethylate lysine-37 of histone H3 (H3K36Me2/3) (Klose et al. 2006).
All characterized lysine demethylases other than KDM1A belong to the jumonjiC domain (JmjC) containing family.The JmjC KDMs are members of the Cupin superfamily of mononuclear Fe (II) dependent oxygenases, which are characterized by the presence of a double-stranded beta-helix core fold. The JmjC KDMs require 2 oxoglutarate (2 OG) and molecular oxygen as co substrates, producing, along with formaldehyde, succinate and carbon dioxide. This hydroxylation based mechanism does not require a protonatable lysine epsilon-amine group and consequently JmjC containing demethylases are able to catalyse demethylateion of tri , di and monomethylated lysines.
KDM3A (JHDM2A), KDM3B (JHDM2B), KDM7A (JHDM1D), PHF8 (JHDM1E) and PHF2 when complexed with ARID5B (Wen et al. 2010, Baba et al. 2011) are specific for mono or di-methylated lysine-10 on histone H3 (H3K9Me1/2) (Yamane et al. 2006, Kim et al. 2012, Horton et al. 2010, Huang et al. 2010, Loenarz et al. 2008, Feng et al. 2010, Fortschegger et al. 2010, Qi et al. 2010).
JMJD6 catalyses demethylation of mono- or di-methylated arginine-3 of histone H3 (H3R2Me1/2) and arginine-4 of histone H4 (H4R3Me1/2) (Chang et al. 2007). Non-histone substrates of JMJD6 arginine demethylation have also been reported (Poulard et al. 2014, Lawrence et al. 2014). Subsequent to its characterization as an arginine demethylase, JMJD6 was reported to be a lysine hydroxylase (Webby et al 2009).
All characterized lysine demethylases other than KDM1A belong to the jumonjiC domain (JmjC) containing family.The JmjC KDMs are members of the Cupin superfamily of mononuclear Fe (II) dependent oxygenases, which are characterized by the presence of a double-stranded beta-helix core fold. The JmjC KDMs require 2 oxoglutarate (2 OG) and molecular oxygen as co substrates, producing, along with formaldehyde, succinate and carbon dioxide. This hydroxylation based mechanism does not require a protonatable lysine epsilon-amine group and consequently JmjC containing demethylases are able to demethylate tri , di and monomethylated lysines.
KDM5A-D (JARID1A-D) catalyse the demethylation of di- or tri-methylated lysine-5 of histone H3 (H3K4Me2/3) (Christensen et al. 2007, Klose et al. 2007, Lee et al. 2007, Secombe et al. 2007, Seward et al. 2007, Iwase et al. 2007).
All characterized lysine demethylases other than KDM1A belong to the jumonjiC domain (JmjC) containing family.The JmjC KDMs are members of the Cupin superfamily of mononuclear Fe (II) dependent oxygenases, which are characterized by the presence of a double-stranded beta-helix core fold. The JmjC KDMs require 2 oxoglutarate (2 OG) and molecular oxygen as co substrates, producing, along with formaldehyde, succinate and carbon dioxide. This hydroxylation based mechanism does not require a protonatable lysine e amine group and consequently JmjC containing demethylases are able to demethylate tri , di and monomethylated lysines. KDM6A (UTX), KDM6B (JMJD3), KDM6C (UTY) and KDM7A (JHDM1D) catalyse the demethylation of di or tri-methylated lysine-28 of histone H3 (H3K27Me2/3) (Agger et al. 2007, Cho et al. 2007, De Santra et al. 2007, Hong et al. 2007, Lan et al. 2007, Lee et al. 2007, Horton et al. 2010, Huang et al. 2010, Walport et al. 2014).
SUV39H1 (KMT1A) and SUV39H2 (KMT1B) and SETDB2 (KMT1F) selectively methylate lysine-10 of histone H3 (H3K9) (Rea et al. 2000, Rice et al. 2003, Falandry et al. 2010). Their predominant activity is conversion of dimethylated H3K9 to trimethylated H3K9 (Peters et al. 2003, Rice et al. 2003, Chin et al. 2006). SETDB1 (ESET, KMT1E) also predominantly methylates dimethylated H3K9 (Schultz et al. 2002), most effectively when complexed with ATF7IP (MCAF, hAM) (Wang et al. 2003).
Methylation of histone H3 lysine-37 (H3K36) is tightly associated with actively transcribed genes and appears to correspond primarily with coding regions (Wagner & Carpenter 2011).
WHSC1 (KMT3G, NSD2, MMSET), a member of the SET2 family, dimethylates H3K36 when provided with nucleosome substrates (Li et al 2009; Qiao et al. 2011). Dimethylation of histone H3 at lysine-37 (H3K36me2) is thought to be the principal chromatin-regulatory activity of WHSC1 (Kuo et al. 2011), SMYD2 (KMT3C) (Brown et al 2006) and NSD1 (KMT3B) (Li et al. 2009, Qiao et al. 2011).
CLOCK is a central element of the core clock mechanism that governs circadian rhythms. It has intrinsic histone acetyltransferase (HAT) activity which regulates the transcription of many clock-controlled genes (Doi et al. 2006, Hirayama et al. 2007). The carboxy-terminal region of CLOCK displays significant sequence homology with the carboxy-terminal domain of NCOA3 (ACTR), which also has intrinsic HAT activity (Chen et al. 1997). CLOCK acetylates histones H3 and H4 with greatest activity at H3K14, lesser activity at H3K9, but does not acetylate H2A and H2B (Doi et al. 2006 and Nakahata et al. 2007).
Tri-methylation of lysine-5 of histone H3 (H3K4) has been linked to transcriptional activation in a variety of eukaryotic species (Ruthenberg et al. 2007). Several H3K4 methyltransferases have been identified in mammals, predominantly members of the Mixed Lineage Leukemia (MLL) protein family. Five of these, KMT2A (MML1), KMT2D (MLL2), KMT2C (MLL3), KMT2B (MLL4) and SETD1A (KMT2F) have been shown to display H3K4 mono-, di- and tri-methyltransferase activity (Milne et al. 2002, Hughes et al. 2004, Cho et al. 2007, Wysocka et al. 2003). KMT2G (SETD1B) is believed to have similar activity on the basis of sequence homology (Ruthenberg et al. 2007). MLLs are a component of large multiprotein complexes that also include WDR5, RBBP5, ASH2 and DPY30, assembled to form the core MLL complex (Nakamura et al. 2002, Hughes et al. 2004, Dou et al. 2006, Tremblay et al. 2014). The WD40 domain of WDR5 recognizes and binds the histone H3 N-terminus, presenting the lysine-4 side chain for methylation by one of the catalytically active MLL family (Couture et al. 2006, Ruthenburg et al. 2006). Histone H3 recognition by WDR5 is regulated by the methylation state of adjacent arginine (H3R2) residue. H3R2 methylation abolishes WDR5 interaction with the H3 histone tail (Couture et al. 2006); H3K4 di-/trimethylation and H3R2 methylation have an inverse relationship (Guccione et al. 2006).
SETD7 (KMT7, SET9, SET7/9) is an H3K4 mono-methytransferase (Wang et al. 2001, Xiao et al. 2003, Hu & Zhang 2006) that can also methylate a wide range of non-histone proteins (Dhayalan et al. 2011). SETD3 can mono- and di-methylate H3K4 and H3K36 (Eom et al. 2011).
SETDB1 (ESET, KMT1E) is one of several protein lysine methyltransferases which selectively methylate lysine-10 of the amino terminus of histone H3 (H3K9) (Rea et al. 2000). It is most effective when complexed with ATF7IP (MCAF, hAM) (Wang et al. 2003).
PRMT1 (Wang et al. 2001, Strahl et al. 2001, Wagner et al. 2006) and PRMT6 (Hyllus et al. 2007) can asymmetrically dimethylate histone H4 at arginine-3 (H4R3me2a). This functions as a transcriptional activation mark that can result in either the recruitment of methyl-binding proteins or the deposition of other posttranslational marks. PRMT1 is the best studied. It is recruited to promoters by a number of different transcription factors (Bedford & Richard 2005). PRMT1-knockout mice die shortly after implantation (Pawlak et al. 2000). In vitro PRMT1 can also methylate histone H2A at arginine-3 (Strahl et al. 2001).
Histone H3 arginine-9 (H3R8) dimethylation is a PRMT5-specific mark (Pal et al. 2004) associated with gene silencing (Chen et al. 1999, Pal et al. 2004, 2007).
PRMT6 is the predominant in vivo methylator of H3R2 (Hyllus et al. 2007, Guccione et al. 2007) and in addition able to methylate arginine-4 of histone H4 (R3H4) and arginine-4 of histone H2A (R3H2A) (Hyllus et al. 2007).
Coactivator-associated arginine methyltransferase 1 (CARM1, PRMT4) predominantly methylates histone H3 at arginine-18 (H3R17) (Ma et al. 2001, Bauer et al. 2002) and to a lesser extent arginine-27 (H3R26) (Schurter et al. 2001, Bauer et al. 2002). In vitro it can also methylate arginine-3, and one or more of four arginines (129/130/132/135) at the C-terminus (Schurter et al. 2001).
PRMT6 (Guccione et al. 2007, Hyllus et al. 2007) and CARM1 (PRMT4) (Schurter et al. 2001, Torres-Padilla et al. 2007) can methylate arginine-3 of histone H3 (H3R2). PRMT6 predominantly asymmetrically dimethylates H3R2 and is the major cellular H3R2 methyltransferase. It has higher activity toward the monomethylated form of the peptide than the unmethylated form (Hyllus et al. 2007).
PRMT5 can methylate histone H4 at arginine-4 (H4R3)and histone H2A at arginine-4 (H2AR3) (Pal et al. 2004). Symmetric dimethylation of histone H4 arginine-4 (H4R3me2s) by PRMT5 is required for subsequent DNA methylation. The histone-binding protein Cooperator of PRMT5 (COPRS) guides PRMT5:WDR77 to methylate histone H4 arginine-4 (H4R3) rather than histone H3 arginine-9 (H3R8) (Lacroix et al. 2008). H4R3me2s serves as a direct binding target for the DNA methyltransferase DNMT3A, which interacts through the ADD domain, which contains a PHD motif (Zhao et al. 2009).
H4R3me2s is a direct binding target for the DNA methyltransferase DNMT3A, which interacts through the ADD domain containing the PHD motif. Loss of the H4R3me2s mark through short hairpin RNA–mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation (Zhao et al. 2009).
PRMT5 can methylate histone H2A at arginine-4 (H2AR3) (Pal et al. 2004). The histone-binding protein cooperator of PRMT5 (COPRS) guides PRMT5:WDR77 to methylate histone H4 arginine-4 (H4R3) rather than histone H3 arginine-9 (H3R8) (Lacroix et al. 2008) and may also be responsible for guiding PRMT5:WDR77 to methylate histone H2A arginine-4 (H2AR3).
Histone H3 is symmetrically dimethylated on arginine-3 by PRMT5 and PRMT7 (Migliori et al. 2012, Tsai et al. 2013). This excludes binding of RBBP7, a central component of the co-repressor complexes Sin3a, NURD and PRC2. Conversely Me2sR3-histone H3 enhances binding of WDR5, a common component of the coactivator complexes MLL, SET1A, SET1B, NLS1 and ATAC. The interaction of histone H3 with WDR5 distinguishes symmetric dimethylation of arginine-3 from asymmetric dimethylation, which inhibits the recruitment of WDR5 to chromatin (Guccione et al. 2007, Hyllus et al. 2007, Migliori et al. 2012).
Symmetric dimethylation of histone H3 arginine-3 (H3R2) enhances binding of WDR5, a component of the coactivator complexes MLL, SET1A, SET1B, NLS1 and ATAC (Migliori et al. 2012).
RBBP7, a central component of the co-repressor complexes Sin3a, NURD and PRC2, can bind histone H3 arginine-3 (H3R2). Symmetrical dimethylation of this residue excludes RBBP7 binding but enhances binding of WDR5, a common component of the coactivator complexes MLL, SET1A, SET1B, NLS1 and ATAC (Migliori et al. 2012).
Coactivator-associated arginine methyltransferase 1 (CARM1, PRMT4) methylates histone H3 at arginine-18 (H3R17) (Ma et al. 2001, Bauer et al. 2002) and to a lesser extent arginine-27 (H3R26) (Schurter et al. 2001, Bauer et al. 2002). In vitro it can also methylate arginine-3, and one or more of four arginines (129/130/132/135) at the C-terminus (Schurter et al. 2001).
PRMT6 methylates histone H2A at arginine-30 (H2AR29). Dimethylation of H2AR29 is specifically enriched at genes repressed by PRMT6, indicating a role for this mark in gene silencing (Waldmann et al. 2011).
Trimethylation of lysine-5 of histone H3 (H3K4) has been linked to transcriptional activation in a variety of eukaryotic species (Ruthenberg et al. 2007). Several H3K4 methyltransferases have been identified in mammals, predominantly members of the Mixed Lineage Leukemia (MLL) protein family. Five of these, KMT2A (MML1), KMT2D (MLL2), KMT2C (MLL3), KMT2B (MLL4) and SETD1A (KMT2F) have been shown to display H3K4 mono-, di- and tri-methyltransferase activity (Milne et al. 2002, Hughes et al. 2004, Cho et al. 2007, Wysocka et al. 2003). KMT2G (SETD1B) is believed to have similar activity on the basis of sequence homology (Ruthenberg et al. 2007). MLLs are a component of large multiprotein complexes that also include WDR5, RBBP5, ASH2 and DPY30, assembled to form the core MLL complex (Nakamura et al. 2002, Hughes et al. 2004, Dou et al. 2006, Tremblay et al. 2014). The WD40 domain of WDR5 recognizes and binds the histone H3 N-terminus, presenting the lysine-4 side chain for methylation by one of the catalytically active MLL family (Couture et al. 2006, Ruthenburg et al. 2006). Histone H3 recognition by WDR5 is regulated by the methylation state of the adjacent arginine (H3R2) residue. H3R2 methylation abolishes WDR5 interaction with the H3 histone tail (Couture et al. 2006); H3K4 di-/trimethylation and H3R2 methylation have an inverse relationship (Guccione et al. 2006).
SMYD3 (KMT3E) and PRDM9 (KMT8B) are able to tri-methylate H3K4 (Hamamoto et al. 2004, Hayashi et al. 2005, Koh-Stenta et al. 2014).
Monomethylation of lysine-21 of histone H4 (H4K20) is performed by SETD8 (KMT5A) (Yin et al. 2005). Trimethylation, performed by SUV420H1 and SUV420H2 and possibly SMYD3 (Foreman et al. 2011), is associated with heterochromatin formation and gene repression (Schotta et al. 2004).
A chromosomal aberration involving the nuclear receptor coactivator NCOA1 and paired box protein Pax-3 (PAX3) is a cause of rhabdomyosarcoma (RMS). Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. RMS is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children (Wachtel et al. 2004).
Chromosomal aberrations involving nuclear receptor coactivator 2 (NCOA2) and histone acetyltransferase KAT6A (KAT6A aka MOZ) may be a cause of acute myeloid leukemias. Inversion inv8(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation (Carapeti et al. 1998).
EHMT2 (KMT1C, G9A) and EHMT1 (KMT1D, GLP) are the euchromatic histone H3 lysine-10 (H3K9) mono and di-methyltransferases in mammals (Tachibana et al. 2002, Rice et al. 2003, Tachibana et al. 2005). In vivo they exist predominantly as a heteromeric complex together with WIZ, a multi-zinc finger protein, (Ueda et al. 2006) and are responsible for global H3K9 mono- and di-methylation (Shinkai & Tchibana 2011).
EHMT2 (KMT1C, G9A) and EHMT1 (KMT1D, GLP) are the euchromatic histone H3 lysine-10 (H3K9) mono and di-methyltransferases in mammals (Tachibana et al. 2002, Rice et al. 2003, Tachibana et al. 2005). In vivo they exist predominantly as a heteromeric complex together with WIZ, a multi-zinc finger protein, (Ueda et al. 2006) and are responsible for global H3K9 mono- and di-methylation (Shinkai & Tchibana 2011).
Trimethylation of lysine-5 of histone H3 (H3K4) has been linked to transcriptional activation in a variety of eukaryotic species (Ruthenberg et al. 2007). Several H3K4 methyltransferases have been identified in mammals, predominantly members of the Mixed Lineage Leukemia (MLL) protein family. Five of these, KMT2A (MML1), KMT2D (MLL2), KMT2C (MLL3), KMT2B (MLL4) and SETD1A (KMT2F) have been shown to display H3K4 mono-, di- and tri-methyltransferase activity (Milne et al. 2002, Hughes et al. 2004, Cho et al. 2007, Wysocka et al. 2003). KMT2G (SETD1B) is believed to have similar activity on the basis of sequence homology (Ruthenberg et al. 2007). MLLs are a component of large multiprotein complexes that also include WDR5, RBBP5, ASH2 and DPY30, assembled to form the core MLL complex (Nakamura et al. 2002, Hughes et al. 2004, Dou et al. 2006, Tremblay et al. 2014). The WD40 domain of WDR5 recognizes and binds the histone H3 N-terminus, presenting the lysine-4 side chain for methylation by one of the catalytically active MLL family (Couture et al. 2006, Ruthenburg et al. 2006). Histone H3 recognition by WDR5 is regulated by the methylation state of the adjacent arginine (H3R2) residue. H3R2 methylation abolishes WDR5 interaction with the H3 histone tail (Couture et al. 2006); H3K4 di-/trimethylation and H3R2 methylation have an inverse relationship (Guccione et al. 2006).
WHSC1L1 (KMT3F, WHISTLE), SMYD3 (KMT3E) and SETD3 are able to di-methylate H3K4 (Kim et al. 2006, Hamamoto et al. 2004, Eom et al. 2011).
SETD2 (KMT3A) trimethylates lysine-37 of histone H3 (H3K36) (Sun et al. 2005) and is thought to be the sole H3K36 methyltransferase in vivo (Edmunds et al. 2008, Yuan et al. 2009).
Methylation of histone H3 lysine-37 (H3K36) is tightly associated with actively transcribed genes and appears to correspond primarily with coding regions (Wagner & Carpenter 2011).
WHSC1 (KMT3G, NSD2, MMSET), a member of the SET2 family, dimethylates H3K36 when provided with nucleosome substrates (Li et al 2009; Qiao et al. 2011). Dimethylation of histone H3 at lysine-37 (H3K36me2) is thought to be the principal chromatin-regulatory activity of WHSC1 (Kuo et al. 2011), SMYD2 (KMT3C) (Brown et al 2006) and NSD1 (KMT3B) (Li et al. 2009, Qiao et al. 2011). ASH1L can perform histone H3 lysine-37 di-methylation (Tanaka et al. 2007, An et al. 2011, Miyazaki et al. 2013, Zhu et al. 2016).
EZH2 (KMT6, PRC2) is the catalytic subunit of the PRC2 (EZH2) Core complex, which additionally contains EED, SUZ12, AEBP2 and one of RBBP4 or RBBP7. It methylates lysine-28 (H3K27) of histone H3 (Cao et al. 2002, Czermin et al. 2002, Kuzmichev et al. 2002, Muller et al. 2002) leading to transcriptional repression of the affected target gene. It is able to mono-, di- and trimethylate lysine-28 (Cao & Zhang 2004).
DOT1L is capable of catalyzing the mono-, di-, and trimethylation of histone H3 in a nonprocessive manner (Min et al. 2003, Frederiks et al. 2008). It appear to be solely responsible for H3K79 methylation, since knockout of Dot1 in yeast, flies and mice results in complete loss of H3K79 methylation (van Leeuwen et al. 2002, Shanower et al. 2005, Jones et al. 2008).
DOT1L is responsible for the mono-, di-, and trimethylation of histone H3 in a nonprocessive manner (Min et al. 2003, Frederiks et al. 2008). It appear to be solely responsible for H3K79 methylation, since knockout of Dot1 in yeast, flies and mice results in complete loss of H3K79 methylation (van Leeuwen et al. 2002, Shanower et al. 2005, Jones et al. 2008).
WHSC1 (MMSET, KMT3G) is able to mono-, di- and trimethylate lysine-28 (Kim et al. 2008). WHSC1L1 (KMT3F, WHISTLE) can di-, and tri-methylate lysine-28 of histone H3 (H3K27) if it has been previously monomethylated at this residue (Kim et al. 2006).
DOT1L is capable of catalyzing mono-, di-, and trimethylation in a nonprocessive manner (Min et al. 2003, Frederiks et al. 2008). It appear to be solely responsible for H3K79 methylation, since knockout of Dot1 in yeast, flies and mice results in complete loss of H3K79 methylation (van Leeuwen et al. 2002, Shanower et al. 2005, Jones et al. 2008).
WHSC1 (MMSET, KMT3G) is able to mono-, di- and trimethylate lysine-28 (Kim et al. 2008). WHSC1L1 (KMT3F, WHISTLE) can di- and tri-methylate lysine-28 of histone H3 (H3K27) if it has been previously methylated at this residue (Kim et al. 2006).
The di- and tri-methylation of lysine-21 of histone H4 (H4K20) are performed by SUV420H1 (KMT5B), SUV420H2 (KMT5C) and possibly SMYD3 (KMT3E) (Foreman et al. 2011). Trimethylation is associated with heterochromatin formation and gene repression (Schotta et al. 2004). Monomethylation is performed by SETD8 (KMT5A) (Yin et al. 2005).
The di- and tri-methylation of lysine-21 of histone H4 (H4K20) are performed by SUV420H1 (KMT5B), SUV420H2 (KMT5C) and possibly SMYD3 (KMT3E) (Foreman et al. 2011). Trimethylation is associated with heterochromatin formation and gene repression (Schotta et al. 2004). Monomethylation is performed by SETD8 (KMT5A) (Yin et al. 2005).
All characterised lysine demethylases other than KDM1A belong to the jumonji C-domain (JmjC) containing family, members of the Cupin superfamily of mononuclear Fe (II)-dependent oxygenases. They require 2-oxoglutarate (2-OG) and molecular oxygen as co-substrates, producing succinate and carbon dioxide. This hydroxylation-based mechanism does not require a protonatable lysine epsilon-amine group and consequently JmjC-containing demethylases are able to demethylate tri-, di- and monomethylated lyines.
The first reported JmjC-containing demethylases were KDM2A and KDM2B (JHDM1A/B, FBXL11/10). These demethylate lysine-37 of histone H3 when mono- or di-methylated (H3K36Me1/2) (Tsukada et al. 2006). KDM4A (JHDM3A) can demethylate mono-, di and trimethylated lysine-37 of histone H3 (Klose et al. 2006). KDM8 can demethylate diimethylated lysine-37 of histone H3 (Hsia et al. 2010).
All characterized lysine demethylases other than KDM1A belong to the jumonjiC domain (JmjC) containing family.The JmjC KDMs are members of the Cupin superfamily of mononuclear Fe (II) dependent oxygenases, which are characterized by the presence of a double-stranded beta-helix core fold. The JmjC KDMs require 2 oxoglutarate (2 OG) and molecular oxygen as co substrates, producing, along with formaldehyde, succinate and carbon dioxide. This hydroxylation based mechanism does not require a protonatable lysine epsilon-amine group and consequently JmjC containing demethylases are able to catalyse demethylateion of tri , di and monomethylated lysines.
KDM3A (JHDM2A), KDM3B (JHDM2B), KDM7A (JHDM1D), PHF8 (JHDM1E) and PHF2 when complexed with ARID5B (Wen et al. 2010, Baba et al. 2011) are specific for mono or di-methylated lysine-10 on histone H3 (H3K9Me1/2) (Yamane et al. 2006, Kim et al. 2012, Horton et al. 2010, Huang et al. 2010, Loenarz et al. 2008, Feng et al. 2010, Fortschegger et al. 2010, Qi et al. 2010).
All characterized lysine demethylases other than KDM1A belong to the jumonjiC domain (JmjC) containing family.The JmjC KDMs are members of the Cupin superfamily of mononuclear Fe (II) dependent oxygenases, which are characterized by the presence of a double-stranded beta-helix core fold. The JmjC KDMs require 2 oxoglutarate (2 OG) and molecular oxygen as co substrates, producing, along with formaldehyde, succinate and carbon dioxide. This hydroxylation based mechanism does not require a protonatable lysine epsilon-amine group and consequently JmjC containing demethylases are able to demethylate tri , di and monomethylated lysines.
KDM5A-D (JARID1A-D) catalyse the demethylation of di- or tri-methylated lysine-5 of histone H3 (H3K4Me2/3) (Christensen et al. 2007, Klose et al. 2007, Lee et al. 2007, Secombe et al. 2007, Seward et al. 2007, Iwase et al. 2007).
Histone H3 arginine-9 (H3R8) dimethylation is a PRMT5-specific mark (Pal et al. 2004) associated with gene silencing (Chen et al. 1999, Pal et al. 2004, 2007).
All characterized lysine demethylases other than KDM1A belong to the jumonjiC domain (JmjC) containing family.The JmjC KDMs are members of the Cupin superfamily of mononuclear Fe (II) dependent oxygenases, which are characterized by the presence of a double-stranded beta-helix core fold. The JmjC KDMs require 2 oxoglutarate (2 OG) and molecular oxygen as co substrates, producing, along with formaldehyde, succinate and carbon dioxide. This hydroxylation based mechanism does not require a protonatable lysine e amine group and consequently JmjC containing demethylases are able to demethylate tri , di and monomethylated lysines. KDM4A-D (JMJD2A-D/JHDM3A-D) catalyse the demethylation of di- or tri-methylated histone H3 at lysine-10 (H3K9Me2/3) (Cloos et al. 2006, Fodor et al. 2006, Whetstine et al. 2007), with a strong preference for Me3 (Whetstine et al. 2007). MINA, a bifunctional histone lysine demethylase and ribosomal histidine hydroxylase, demethylates trimethylated lysine-10 of histone H3 (Lu et al. 2009).
KDM4A (JHDM3A) can also demethylate lysine-37 of histone H3 (H3K36Me2/3) (Klose et al. 2006).
All characterized lysine demethylases other than KDM1A belong to the jumonjiC domain (JmjC) containing family.The JmjC KDMs are members of the Cupin superfamily of mononuclear Fe (II) dependent oxygenases, which are characterized by the presence of a double-stranded beta-helix core fold. The JmjC KDMs require 2 oxoglutarate (2 OG) and molecular oxygen as co substrates, producing, along with formaldehyde, succinate and carbon dioxide. This hydroxylation based mechanism does not require a protonatable lysine e amine group and consequently JmjC containing demethylases are able to demethylate tri , di and monomethylated lysines. KDM6A (UTX), KDM6B (JMJD3), KDM6C (UTY) and KDM7A (JHDM1D) catalyse the demethylation of di or tri-methylated lysine-28 of histone H3 (H3K27Me2/3) (Agger et al. 2007, Cho et al. 2007, De Santra et al. 2007, Hong et al. 2007, Lan et al. 2007, Lee et al. 2007, Horton et al. 2010, Huang et al. 2010, Walport et al. 2014).
JMJD6 catalyses demethylation of mono- or di-methylated arginine-3 of histone H3 (H3R2Me1/2) and arginine-4 of histone H4 (H4R3Me1/2) (Chang et al. 2007). Non-histone substrates of JMJD6 arginine demethylation have also been reported (Poulard et al. 2014, Lawrence et al. 2014). Subsequent to its characterization as an arginine demethylase, JMJD6 was reported to be a lysine hydroxylase (Webby et al 2009).
Histone demethylases (HDMs) belong to two groups with distinct catalytic mechanisms. KDM1A and KDM1B (formerly known as Lysine Specific Demethylases 1 and 2), belong to the flavin adenine dinucleotide (FAD)-dependent amino oxidase family, releasing formaldehyde. The reaction mechanism requires a protonatable lysine epsilon-amino group, not available in trimethylated lysines (Shi et al. 2004). KDM1A and subsequently KDM1B were shown to catalyse demethylation of monomethyl and dimethyl, but not trimethyl, histone H3 at lysine 5 (H3K4) in vitro (Shi et al. 2004, Ciccone et al. 2009). Subsequently KDM1A was found to be much more proficient at catalysing demethylation of H3K4 when part of a multiprotein complex (Lee et al. 2005) and shown to catalyse demethylation of histone H3 at lysine 10 (H3K9) in vivo when associated with the androgen receptor (Metzger et al. 2007), suggesting that its substrate specificity is modulated by interacting proteins. KDM1A is a subunit of several complexes, including CtBP, Co-REST, NRD and BRAF35 (Lan et al. 2008). It is also able to catalyse demethylation of a number of non-histone proteins (Nicholson & Chen 2009).
JMJD6 catalyses demethylation of mono- or di-methylated arginine-3 of histone H3 (H3R2Me1/2) and arginine-4 of histone H4 (H4R3Me1/2) (Chang et al. 2007). Non-histone substrates of JMJD6 arginine demethylation have also been reported (Poulard et al. 2014, Lawrence et al. 2014). Subsequent to its characterization as an arginine demethylase, JMJD6 was reported to be a lysine hydroxylase (Webby et al 2009).
JMJD6 catalyses demethylation of mono- or di-methylated arginine-3 of histone H3 (H3R2Me1/2) and arginine-4 of histone H4 (H4R3Me1/2) (Chang et al. 2007). Non-histone substrates of JMJD6 arginine demethylation have also been reported (Poulard et al. 2014, Lawrence et al. 2014). Subsequent to its characterization as an arginine demethylase, JMJD6 was reported to be a lysine hydroxylase (Webby et al 2009).
PRMT1 (Wang et al. 2001, Strahl et al. 2001, Wagner et al. 2006) and PRMT6 (Hyllus et al. 2007) can asymmetrically dimethylate histone H4 at arginine-3 (H4R3me2a). This functions as a transcriptional activation mark that can result in either the recruitment of methyl-binding proteins or the deposition of other posttranslational marks. PRMT1 is the best studied. It is recruited to promoters by a number of different transcription factors (Bedford & Richard 2005). PRMT1-knockout mice die shortly after implantation (Pawlak et al. 2000). In vitro PRMT1 can also methylate histone H2A at arginine-3 (Strahl et al. 2001).
SET domain containing 6 (SETD6) is an N-lysine methyltransferase that monomethylates the RelA subunit of nuclear factor kappa B (NF-kB) at Lys-310 (Levy et al. 2011, Chang et al. 2011).
BRWD1 (WDR9) is a nuclear protein with eight WD repeats at the N-terminus and 2 centrally located bromodomains. BRWD1 is thought to be involved in chromatin remodelling and transcriptional regulation. BRWD1 binds to Transcription activator BRG1 (SMARCA4 or BRG1), a component of the SWI/SNF complex(Huang et al. 2003). Similar to BRWD1 (Mandal et al. 2015), SMARCA4 is also implicated in B-cell development (Choi et al. 2012, Bossen et al. 2015).
Human Bromodomain and WD repeat-containing protein 1 (BRWD1) binds to histone H3 acetylated at lysine residues K9, K14, K18 and K79 and phosphorylated at serine residue S10 and threonine residue T11 in various combinations in vitro (Filippakopoulos et al. 2012). In mouse, it was confirmed that BRWD1 interacts with histone H3 acetylated at lysine residues K9 and K14, and phosphorylated at serine residue S10 (Mandal et al. 2015). Please note that the listed amino acid residues in mature histone H3 match nascent histone H3 residues K10, K15, K19, K80, S11 and T12, respectively. Amino acid positions in Reactome annotations of modified residues and Reactome systematic names correspond to positions in the nascent protein UniProt sequence.
Protein arginine methyltransferase 3 (PRMT3) is a cytosolic enzyme that catalyzes the formation of omega-mono- or asymmetric dimethylarginine (Tang et al. 1998). It has a unique substrate binding N-terminal C2H2 Zn finger domain and a catalytic C-terminal domain that is homologous to other PRMTs (Zhang et al. 2000). PRMT3 associates with ribosomes in the cytosol, which contain its main in vivo substrate, the small ribosomal subunit Ribosomal protein S2 (RPS2). PRMT3 methylates arginines in the RG-rich N-terminal tail of RPS2 forming asymmetric dimethylarginines (Swiercz et al. 2005). Prmt3–null mice show developmental delay during embryogenesis and have embryos that are markedly smaller than wt , though size at birth is normal suggesting that PRMT3 loss can be compensated for in most cell types but may not be in under conditions that demand extremely fast protein synthesis (Swiercz et al. 2007).
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histone H3, Cit9-replicative histone H3, Cit18-replicative histone H3, Cit27-replicative
histone H3histone H3, MeR9-replicative histone H3, MeR18-replicative histone H3, Me27-replicatve
histone H3WHSC1L1, Core MLL
complexchromatin remodelling
complex:PRMT5:pT5-WDR77complex, SMYD3,
SETD3Annotated Interactions
histone H3, Cit9-replicative histone H3, Cit18-replicative histone H3, Cit27-replicative
histone H3histone H3, MeR9-replicative histone H3, MeR18-replicative histone H3, Me27-replicatve
histone H3Subsequently KDM1A was found to be much more proficient at catalysing demethylation of H3K4 when part of a multiprotein complex (Lee et al. 2005) and shown to catalyse demethylation of histone H3 at lysine 10 (H3K9) in vivo when associated with the androgen receptor (Metzger et al. 2007), suggesting that its substrate specificity is modulated by interacting proteins. KDM1A is a subunit of several complexes, including CtBP, Co-REST, NRD and BRAF35 (Lan et al. 2008). It is also able to catalyse demethylation of a number of non-histone proteins (Nicholson & Chen 2009).
SWI/SNF complexes are a family of ATP-dependent chromatin remodelling complexes involved in the activation and repression of gene transcription. They generate nucleosomes with altered positions, nucleosomes with DNA loops and nucleosomes that are capable of exchanging histone dimers or octamers (Racki & Narlikar 2008).
The core of the hSWI/SNF complex contains SMARCA4 (BRG1/BAF190A) or SMARCA2 (hBrm/BAF190B), SMARCC1 (BAF155), SMARCC2 (BAF170) and SMARCB1 (INI1) plus a variable number of additional subunits (Wang et al. 1996, Phelan et al. 1999, Reisman et al. 2009). SMARCA4 or SMARCA2 are the catalytic ATPase subunits. SMARCC1 and SMARCC2 are 62% identical to each other at the protein level (Wang et al. 1996). Loss of the SMARCB1 subunit (SWI/SNF-related matrix associated actin dependent regulator of chromatin B1) is a recurrent genetic characteristic of malignant rhabdoid tumor (MRT), a rare and aggressive pediatric cancer (Versteege et al. 1998, Biegel et al.1999). SMARCB1 mouse knockouts cause early embryonic lethality; heterozygous loss predisposes mice to MRT-like tumors (Klochendler-Yeivin et al. 2000, Roberts et al. 2000, Guidi et al. 2001). Actin and actin-related proteins found in hSWI/SNF complexes and are believed to facilitate nuclear matrix association (Zhao et al. 1998, Rando et al. 2002).
Dysregulation of PADI activity is associated with a range of diseases, including rheumatoid arthritis (RA), multiple sclerosis, ulcerative colitis, neural degeneration, COPD, and cancer (Lange et al. 2011, McElwee et al. 2012).
The SAGA complex consists of KAT2A (hGCN5), TADA1 (STAF42), TADA2B (ADA2b), TADA3 (STAF54, ADA3), SUPT3H (SPT3), SUPT7L (STAF65G), TAF5L (PAF65B), TAF6L (PAF65A), TAF9 (TAFII31), TAF12 (TAFII20), TAF10 (TAFII31), TRRAP, SAP130 (Martinez et al. 2001), CCDC101, ATXN7, a factor termed STAF55 that cannot be identified, two further factors described as probable members that cannot be identified STAF46 and STAF60 (Nagy & Tora 2007) plus ATXN7L3, USP22, ENY2 (Zhao et al. 2008) and SUPT20H (Nagy et al. 2009).
N.B. Coordinates of post-translational modifications described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
The Elongator complex is directed specifically toward the N-terminal tails of histones H3 and H4, favouring acetylation at lysine-14 (K14) of histone H3 and lysine-8 (K8) of histone H4 (Winkler et al. 2002).
Yeast Elp3 nulls exhibit slow activation of certain genes and defects in histone H3 acetylation patterns essential for gene activation (Kristjuhan et al. 2002, Winkler et al. 2002, Kristjuhan & Svejstrup 2004). Elp3 is essential for the association of Elongator with nascent RNA in vivo (Petrakis et al. 2004; Svejstrup 2007).
Misregulation of ELP3 is implicated in human disorders that affect neuronal function, including familial dysautonomia (FD), an autosomal recessive neurodevelopmental disease characterized by degeneration of the sensory and autonomic nervous system (Slaugenhaupt & Gusella 2002, Simpson et al. 2009), and the motor neuron degenerative disorder amyotrophic lateral sclerosis (ALS) (Wallis et al. 2008). In mammalian cells Elp3 is essential for promoting transcription-activating histone H3 acetylation in the coding regions of certain neuronal cell motility genes (Close et al. 2006).
Human INGs can be divided into three groups: ING1/2, ING3, and ING4/5, based on their association with three distinct types of protein complexes (Doyon et al. 2006). All regulate chromatin via histone acetylation and deacetylation. The catalytic histone acetyltransferase (HAT) subunits of ING complexes are members of the MYST family, KAT5 (Tip60), KAT7 (HBO1) KAT6A (MOZ), KAT6B (MORF), and KAT8 (MOF). ING4 exists in vivo as a dimer, binding two lysine-4 trimethylated histone H3 (H3K4me3) modifications (Palacios et al. 2010). Homology modeling suggests that other INGs are likely to be dimers (Culurgioni et al. 2012).
KAT7-ING4/5 complexes interact with lysine-4 trimethylated histone H3 (H3K4me3), acetylating surrounding histone tails to stimulate local transcription (Palacios et al. 2008, Champagne et al. 2008, Hung et al. 2009, Saksouk et al. 2009).
KAT6A and KAT6B have intrinsic histone acetyltransferase activity (Champagne et al. 1999, 2001). Both can form tetrameric 'ING5' complexes with BRPF1 (possibly BRPF2 and 3), EAF6 and ING5. BRPF1 and EAF6 drastically stimulate the acetyltransferase activities of KAT6A/B against nucleosomal histone H3 (Doyon et al. 2006, Ullah et al. 2008). ING5-MOZ/MORF complexes acetylate only histone H3 at lysine-14.
KAT6A homozygous mice die at birth, with reduced hematopoiesis and profound defects in the stem cell compartment. These mice have no long-term repopulating stem cells and display substantial reduction in the number of multipotent cells able to form spleen colonies (Thomas et al. 2006). Chromosomal rearrangements of the KAT6A gene are associated with acute myeloid leukemia (AML), uterine leiomyomata and therapy-related myelodysplastic syndromes (Yang & Ullah, 2007).
Mutations in KAT6B are the cause of the Say-Barber-Biesecker variant of Ohdo syndrome and Genitopatellar syndrome (Campeau et al. 2012, Szakszon et al. 2013).
NSL acetylates histone H4 on lysines 17 (H4K16), 6 (H4K5) and 9 (H4K8) (Cai et al. 2010).
KAT8 is also the catalytic subunit of the male-specific lethal (MSL) complex, which acetylates almost exclusively H4K16 and is responsible for a large fraction of H4K16 acetylation in human cells (Smith et al. 2005).
N.B. Coordinates of post-translational modifications described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
N.B. Coordinates of post-translational modifications described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
CREBBP has intrinsic histone acetyltransferase (HAT) activity on lysine-13 of H2B, lysine-15 of H3 and lysine-9 of H4 (Bannister & Kouzarides 1996, Rekowski & Giannis 2010, Barrett et al. 2011).
Homozygous knockout of CREBBP results in embryonic lethality (Tanaka et al. 1997). Focal deletion of CREBBP demonstrates that it is critical for the in vivo acetylation of lysines on histones H2B, H3 and H4, and cannot be compensated for by the p300 (Barrett et al. 2011).
Genomic aberrations in CREBBP are associated with Rubinstein-Taybi syndrome (Torress et al. 2013).
N.B. Coordinates of post-translational modifications described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
The Sin3B complex shares some subunits in common with the Sin3A complex but may also contain distinct subunits (Le Guezennec et al. 2006a).
The NuRD complex contains a core histone deacetylase complex that consists of the HDAC1-2 catalytic core plus RBBP7 (RbAp46) and RBBP4 (RbAp48) (Ahringer 2000). The largest and key component is the Mi-2 remodelling subunit (dermatomyositis-specific autoantigen), which contains the ATPase/chromatin remodelling activity and physically associates with the other components. Mammals have two Mi-2 proteins: CHD3 (Mi-2alpha), and CHD4 (Mi-2 beta) (Seelig et al. 1996). CHD4 (Mi-2 beta) is the form predominantly associated with the NuRD complex (Zhang et al. 1998, Feng & Zhang 2001), although CHD3 is a member of the NuRD complex in a variety of human cell lines (Le Guezennec et al. 2006b). It is not clear whether functional differences exist between CHD3 and CHD4-containing complexes (McDonel et al. 2009). Further components are MBD3 (methyl CpG-binding domain 3), and a metastasis-associated (MTA) protein subunit. MTA subunits (e.g. Mta1, Mta2 or Mta3) appear to be mutually exclusive, possibly contributing to functional diversity of NuRD complexes (Bowen et al. 2004, Fujita et al. 2004). GATAD2A and GATAD2B proteins (formerly known as p66alpha and p66beta) are often reported as members of NuRD. MBD3 can be replaced by related protein MBD2, forming the MeCP1 complex (Feng & Zhang 2001, Le Guezennec et al. 2006b). The MeCP1 complex represents only a small proportion of the total NuRD complex in mammalian cells (Refs. in McDonel et al. 2009); MBD2 has been shown to be dispensable for normal mammalian development (Hendrich et al. 2001).
NuRD is recruited via MDB3 for DNA methylation-dependent gene silencing. It associates with MeCP1 (methyl CpG-binding protein 1) and MeCP2 to provide an intimate connection with DNA methylation (Denslow & Wade 2007, Klose & Bird 2006).
The CoREST complex minimally contains the HDAC1-2 catalytic core, REST (RE1-silencing transcription factor), RCOR1 (CoREST, KIAA0071) and KDM1A (BHC110, LSD1) (Andres et al. 1999, Humphrey et al. 2001). The BRAF–HDAC (BHC) complex consists of HDAC1-2, RCOR1, KDM1A, HMG20B (BRAF35) and PHF21A (BHC80) (Hakimi et al. 2002, Yang & Seto 2008).
This reaction represents a theoretical complete deacetylation of histone.
The first reported JmjC-containing demethylases were KDM2A and KDM2B (JHDM1A/B, FBXL11/10). These demethylate lysine-37 of histone H3 when mono- or di-methylated (H3K36Me1/2) (Tsukada et al. 2006). KDM4A (JHDM3A) can demethylate mono-, di and trimethylated lysine-37 of histone H3 (Klose et al. 2006). KDM8 can demethylate diimethylated lysine-37 of histone H3 (Hsia et al. 2010).
KDM4A-D (JMJD2A-D/JHDM3A-D) catalyse the demethylation of di- or tri-methylated histone H3 at lysine-10 (H3K9Me2/3) (Cloos et al. 2006, Fodor et al. 2006, Whetstine et al. 2007), with a strong preference for Me3 (Whetstine et al. 2007). MINA, a bifunctional histone lysine demethylase and ribosomal histidine hydroxylase, demethylates trimethylated lysine-10 of histone H3 (Lu et al. 2009). KDM4A (JHDM3A) can also demethylate lysine-37 of histone H3 (H3K36Me2/3) (Klose et al. 2006).
KDM6A (UTX), KDM6B (JMJD3), KDM6C (UTY) and KDM7A (JHDM1D) catalyse the demethylation of di or tri-methylated lysine-28 of histone H3 (H3K27Me2/3) (Agger et al. 2007, Cho et al. 2007, De Santra et al. 2007, Hong et al. 2007, Lan et al. 2007, Lee et al. 2007, Horton et al. 2010, Huang et al. 2010, Walport et al. 2014).
WHSC1 (KMT3G, NSD2, MMSET), a member of the SET2 family, dimethylates H3K36 when provided with nucleosome substrates (Li et al 2009; Qiao et al. 2011). Dimethylation of histone H3 at lysine-37 (H3K36me2) is thought to be the principal chromatin-regulatory activity of WHSC1 (Kuo et al. 2011), SMYD2 (KMT3C) (Brown et al 2006) and NSD1 (KMT3B) (Li et al. 2009, Qiao et al. 2011).
SETD7 (KMT7, SET9, SET7/9) is an H3K4 mono-methytransferase (Wang et al. 2001, Xiao et al. 2003, Hu & Zhang 2006) that can also methylate a wide range of non-histone proteins (Dhayalan et al. 2011). SETD3 can mono- and di-methylate H3K4 and H3K36 (Eom et al. 2011).
SMYD3 (KMT3E) and PRDM9 (KMT8B) are able to tri-methylate H3K4 (Hamamoto et al. 2004, Hayashi et al. 2005, Koh-Stenta et al. 2014).
The first reported JmjC-containing demethylases were KDM2A and KDM2B (JHDM1A/B, FBXL11/10). These demethylate lysine-37 of histone H3 when mono- or di-methylated (H3K36Me1/2) (Tsukada et al. 2006). KDM4A (JHDM3A) can demethylate mono-, di and trimethylated lysine-37 of histone H3 (Klose et al. 2006). KDM8 can demethylate diimethylated lysine-37 of histone H3 (Hsia et al. 2010).
KDM4A-D (JMJD2A-D/JHDM3A-D) catalyse the demethylation of di- or tri-methylated histone H3 at lysine-10 (H3K9Me2/3) (Cloos et al. 2006, Fodor et al. 2006, Whetstine et al. 2007), with a strong preference for Me3 (Whetstine et al. 2007). MINA, a bifunctional histone lysine demethylase and ribosomal histidine hydroxylase, demethylates trimethylated lysine-10 of histone H3 (Lu et al. 2009). KDM4A (JHDM3A) can also demethylate lysine-37 of histone H3 (H3K36Me2/3) (Klose et al. 2006).
KDM6A (UTX), KDM6B (JMJD3), KDM6C (UTY) and KDM7A (JHDM1D) catalyse the demethylation of di or tri-methylated lysine-28 of histone H3 (H3K27Me2/3) (Agger et al. 2007, Cho et al. 2007, De Santra et al. 2007, Hong et al. 2007, Lan et al. 2007, Lee et al. 2007, Horton et al. 2010, Huang et al. 2010, Walport et al. 2014).
Subsequently KDM1A was found to be much more proficient at catalysing demethylation of H3K4 when part of a multiprotein complex (Lee et al. 2005) and shown to catalyse demethylation of histone H3 at lysine 10 (H3K9) in vivo when associated with the androgen receptor (Metzger et al. 2007), suggesting that its substrate specificity is modulated by interacting proteins. KDM1A is a subunit of several complexes, including CtBP, Co-REST, NRD and BRAF35 (Lan et al. 2008). It is also able to catalyse demethylation of a number of non-histone proteins (Nicholson & Chen 2009).
WHSC1L1, Core MLL
complexchromatin remodelling
complex:PRMT5:pT5-WDR77chromatin remodelling
complex:PRMT5:pT5-WDR77chromatin remodelling
complex:PRMT5:pT5-WDR77complex, SMYD3,
SETD3