Transcriptional regulation by MECP2 (Homo sapiens)

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1-6, 8, 10...37, 8464364279, 99996032, 448156, 6437, 6217, 32889441, 75844, 95368, 4360clathrin-sculpted gamma-aminobutyric acid transport vesicle membranenucleoplasmcytosolMECP2:PPARG geneDLL1 genePTEN mRNA TBL1XR1 MECP2_e1 MECP2_e1 MECP2_e1 SLC2A3 gene MECP2_e2 HDAC1 CREB1 geneEIF2C3 MECP2_e1 MECP2_e2 MECP2_e2 MECP2:GAMT geneTNRC6B SomatostatinDLL1MECP2_e1 OPRK1 geneMECP2:OPRK1 geneMECP2_e1 5hmC-DNAHDAC1 MECP2_e2 MECP2:p-S133-CREB1:SLC2A3 geneCRHMECP2_e1 SGK1EIF2C3 HDAC1 MECP2_e1 miR-132 RISCMECP2_e2 MECP2_e1 mRNA TRPC3 geneNCOR2 MIR137 gene MECP2:CRH geneMECP2:NCoR/SMRTcomplexGRIA2SGK1 gene MECP2_e1 RBFOX1MECP2 mRNA:miR-132RISCMECP2:MEF2C geneMECP2_e2 MECP2_e1 PPARGMECP2:IRAK1 geneGAMT geneMECP2_e2 miR-137 CREB1 gene DGCR8TNRC6A MECP2_e1 GRIN2A geneSIN3A MECP2:DGCR8SIN3A MECP2:CREB1 genep-S80-MECP2_e2 MECP2:SIN3A:HDAC1MECP2_e2 MECP2_e2 MECP2_e1 PTPN1 gene HIPK2PTENEIF2C4 p-S435-MECP2_e1 TBL1X MECP2_e1 MECP2_e1 MECP2_e1 EIF2C3 HDAC2 IRAK1 gene MECP2_e2 NCoR/SMRT complexPre-NOTCH Expressionand ProcessingDLL1 gene MECP2_e2 MECP2_e2 SLC2A3 gene5mC-DNAFKBP5GRIN2B geneMIR132 geneNOTCH1 gene TNRC6C NCOR1 p-S133-CREB1:MIR132geneEIF2C1 SIN3A:HDAC1,HDAC2dimersGRIN2AHTTHDAC2 GPRIN1 geneMECP2_e1 EIF2C1 MECP2_e2 p-S80-MECP2_e2 MOBPGAD2 geneFKBP5 geneAURKBMECP2_e1 MECP2:SIN3A:HDAC1,HDAC2miR-132-5p p-S92-MECP2_e1 MECP2:GRIN2A geneHDAC1 PRKACA MECP2:LBRTNRC6B miR-137 RISCMECP2:SIN3A:HDAC1:HDAC2:GRIA2 geneGRIN2A gene MECP2_e2 MECP2_e2 p-S133-CREB1 PTEN mRNA:miR-137RISCMECP2:FKBP5 geneSOX2 GPS2 Signaling by NOTCHPVALB gene PVALBMECP2_e1 EIF2C4 p-S423-MECP2_e2 GAD2CRH geneMECP2_e2 OPRM1OPRK1MECP2_e1 MECP2_e2 MECP2_e1 RBFOX1 geneNCOR2 p-T287-CAMK2D MECP2:5mC-DNASIN3A MECP2_e1 NOTCH1 geneMECP2_e1 SLC2A3RBFOX1 gene AGO2 MECP2:HTTGPRIN1 gene SST(89-116) MECP2_e1 miR-132-5p MECP2_e1 PTEN mRNAMECP2:SGK1 geneTRPC3 gene HDAC3 MECP2 mRNABDNF gene PTPN1AGO2 MECP2_e2 MECP2_e1 FOXG1 MECP2_e2 HDAC1 MECP2_e2 HDAC3 MECP2_e2 EIF2C4 MECP2_e2 SIN3A MECP2_e2 HDAC1 HDAC2 NCOR1 GAMTActive PRKACA,CaMKIVTRPC3(1-848)MECP2:GRIN2B geneMECP2:DLL1 geneMECP2_e2 MECP2_e2 MECP2_e2 SST gene DGCR8 PVALB geneGAMT gene miR-137 MECP2_e2 MECP2:NOTCH1 geneMETp-T308-MECP2EIF2C1 EIF2C4 MECP2:MET geneHDAC2 MECP2:FOXG1SIN3A MECP2SGK1 geneMOV10 FKBP5 gene p-T287-CAMK2G MEF2CGRIN2B gene BDNF geneMECP2_e2 MOV10 HTT MECP2:MOBP geneMECP2_e1 p-S133-CREB1 5hmC-DNA MECP2_e2 MECP2_e2 TNRC6A MEF2C genep-S92-MECP2_e1 p-S80-MECP2SIN3A IRAK1 geneMECP2_e2 TNRC6A MECP2_e2 p-T286-CAMK2A MECP2_e1 CALM1 PTPN4 gene TNRC6B GRIA2 gene MECP2:PVALB genePTPN4 geneMOV10 MET geneMIR137 geneMECP2_e1 MECP2_e2 GRIA2 genep-S423-MECP2LBR GAD1 gene MECP2_e2 TNRC6C p-T320-MeCP2_e1 MECP2:GAD1 geneMECP2:p-S133-CREB1TNRC6A MECP2_e2 SIN3A MECP2:GPRIN1 geneMECP2:SIN3A:HDAC1:HDAC2MECP2_e1 p-T308-MECP2_e2 CREB1TNRC6B MECP2:PTPN4 genePPARG geneMET gene TNRC6C BDNFPTPN1 geneMECP2:p-S133-CREB1:SST geneMECP2:SIN3A:HDAC1:BDNF genep-S133-CREB1 EIF2C3 p-S133-CREB1 FOXG1SOX2LBREIF2C1 CALM1 MECP2_e1 p-T287-CAMK2B MECP2:PTPN1 geneMECP2_e2 GAD2 gene CAMK4 MECP2_e1 GAD1MECP2_e2 AGO2 5mC-DNA MOBP gene CAMK4 MECP2_e2 AGO2 MECP2:GAD2 geneMECP2_e1 mRNA MIR132 gene TBL1XR1 MECP2_e1 Ca2+ IRAK1MECP2_e2 mRNA MOBP geneOPRM1 geneSST(103-116) MECP2:TRPC3 geneOPRK1 gene GAD1 geneMECP2:RBFOX1 geneOPRM1 gene MECP2:SOX2:MIR137geneMECP2_e2 mRNA PPARG gene MECP2_e1 Active CaMK IV,(CaMKII)GRIN2BTNRC6C MECP2_e2 ATPGPS2 HDAC1 MECP2_e1 ADPMECP2_e1 MECP2_e2 MECP2_e1 PTPN4MECP2_e1 p-S133-CREB1 CRH gene MEF2C gene Ca2+ TBL1X NOTCH1 mRNAMOV10 MECP2_e1 MECP2:SIN3A:HDAC1:HDAC1:OPRM1 geneMECP2:5hmC-DNAMECP2_e1 MECP2_e1 SST genep-S133-CREB1homodimerHDAC2 GPRIN183535353535356017643535357, 9, 12, 15, 18...3535763535353535353564353583535353535353535353535353535353535743535353535353540, 933535353575353535353535353535353535353535353536353535353594353535353535353535353535353535353535


Description

MECP2 is an X chromosome gene whose loss-of-function mutations are an underlying cause of the majority of Rett syndrome cases. The MECP2 gene locus consists of four exons. Both exon 1 and exon 2 contain translation start sites. Alternative splicing of the second exon results in expression of two MECP2 transcript isoforms, MECP2_e1 (MECP2B or MECP2alpha) and MECP2_e2 (MECP2A or MECP2beta). The N-terminus of the MECP2_e1 isoform, in which exon 2 is spliced out, is encoded by exon 1. The N-terminus of the MECP2_e2 isoforms, which includes both exon 1 and exon 2, is encoded by exon 2, as the exon 2 translation start site is used. Exons 3 and 4 are present in both isoforms. The MECP2_e2 isoform was cloned first and is therefore more extensively studied. The MECP2_e1 isoform is more abundant in the brain (Mnatzakanian et al. 2004, Kriaucionis and Bird 2004, Kaddoum et al. 2013). Mecp2 isoforms show different expression patterns during mouse brain development and in adult brain regions (Dragich et al. 2007, Olson et al. 2014). While Rett syndrome mutations mainly occur in exons 3 and 4 of MECP2, thereby affecting both MECP2 isoforms (Mnatzakanian et al. 2004), some mutations occur in exon 1, affecting MECP2_e1 only. No mutations have been described in exon 2 (Gianakopoulos et al. 2012). Knockout of Mecp2_e1 isoform in mice, through a naturally occurring Rett syndrome point mutation which affects the first translation codon of MECP2_e1, recapitulates Rett-like phenotype. Knockout of Mecp2_e2 isoform in mice does not result in impairment of neurologic functions (Yasui et al. 2014). In Mecp2 null mice, transgenic expression of either Mecp2_e1 or Mecp2_e2 prevents development of Rett-like phenotype, with Mecp2_e1 rescuing more Rett-like symptoms than Mecp2_e2. This indicates that both splice variants can fulfill basic Mecp2 functions in the mouse brain (Kerr et al. 2012). Changes in gene expression upon over-expression of either MECP2_e1 or MECP2_e2 imply overlapping as well as distinct target genes (Orlic-Milacic et al. 2014).

Methyl-CpG-binding protein 2 encoded by the MECP2 gene binds to methylated CpG sequences in the DNA. The binding is not generic, however, but is affected by the underlying DNA sequence (Yoon et al. 2003). MECP2 binds to DNA containing 5 methylcytosine (5mC DNA), a DNA modification associated with transcriptional repression (Mellen et al. 2012), both in the context of CpG islands and outside of CpG islands (Chen et al. 2015). In addition, MECP2 binds to DNA containing 5 hydroxymethylcytosine (5hmC DNA), a DNA modification associated with transcriptional activation (Mellen et al. 2012). MECP2 binds to DNA as a monomer, occupying about 11 bp of the DNA. Binding of one MECP2 molecule facilitates binding of the second MECP2 molecule, and therefore clustering can occur at target sites. MECP2 binding to chromatin may be facilitated by nucleosome methylation (Ghosh et al. 2010).<p>MECP2 was initially proposed to act as a generic repressor of gene transcription. However, high throughput studies of MECP2-induced changes in gene expression in mouse hippocampus (Chahrour et al. 2008), and mouse and human cell lines (Orlic-Milacic et al. 2014) indicate that more genes are up-regulated than down-regulated when MECP2 is overexpressed. At least for some genes directly upregulated by MECP2, it was shown that a complex of MECP2 and CREB1 was involved in transcriptional stimulation (Chahrour et al. 2008, Chen et al. 2013).<p>MECP2 expression is the highest in postmitotic neurons compared to other cell types, with MECP2 being almost as abundant as core histones. Phosphorylation of MECP2 in response to neuronal activity regulates binding of MECP2 to DNA, suggesting that MECP2 may remodel chromatin in a neuronal activity-dependent manner. The resulting changes in gene expression would then modulate synaptic plasticity and behavior (reviewed by Ebert and Greenberg 2013). In human embryonic stem cell derived Rett syndrome neurons, loss of MECP2 is associated with a significant reduction in transcription of neuronally active genes, as well as the reduction in nascent protein synthesis. The reduction in nascent protein synthesis can at least in part be attributed to the decreased activity of the PI3K/AKT/mTOR signaling pathway. Neuronal morphology (reduced soma size) and the level of protein synthesis in Rett neurons can be ameliorated by treating the cells with growth factors which activate the PI3K/AKT/mTOR cascade or by inhibition of PTEN, the negative regulator of AKT activation. Mitochondrial gene expression is also downregulated in Rett neurons, which is associated with a reduced capacity of the mitochondrial electron transport chain (Ricciardi et al. 2011, Li et al. 2013). Treatment of Mecp2 null mice with IGF1 (insulin-like growth factor 1) reverses or ameliorates some Rett-like features such as locomotion, respiratory difficulties and irregular heart rate (Tropea et al. 2009).<p>MECP2 regulates expression of a number of ligands and receptors involved in neuronal development and function. Ligands regulated by MECP2 include BDNF (reviewed by Li and Pozzo-Miller 2014, and KhorshidAhmad et al. 2016), CRH (McGill et al. 2006, Samaco et al. 2012), SST (Somatostatin) (Chahrour et al. 2008), and DLL1 (Li et al. 2014). MECP2 also regulates transcription of genes involved in the synthesis of the neurotransmitter GABA – GAD1 (Chao et al. 2010) and GAD2 (Chao et al. 2010, He et al. 2014). MECP2 may be involved in direct stimulation of transcription from the GLUD1 gene promoter, encoding mitochondrial glutamate dehydrogenase 1, which may be involved in the turnover of the neurotransmitter glutamate (Livide et al. 2015). Receptors regulated by MECP2 include glutamate receptor GRIA2 (Qiu et al. 2012), NMDA receptor subunits GRIN2A (Durand et al. 2012) and GRIN2B (Lee et al. 2008), opioid receptors OPRK1 (Chahrour et al. 2008) and OPRM1 (Hwang et al. 2009, Hwang et al. 2010, Samaco et al. 2012), GPRIN1 (Chahrour et al. 2008), MET (Plummer et al. 2013), NOTCH1 (Li et al. 2014). Channels/transporters regulated by MECP2 include TRPC3 (Li et al. 2012) and SLC2A3 (Chen et al. 2013). MECP2 regulates transcription of FKBP5, involved in trafficking of glucocorticoid receptors (Nuber et al. 2005, Urdinguio et al. 2008). MECP2 is implicated in regulation of expression of SEMA3F (semaphorin 3F) in mouse olfactory neurons (Degano et al. 2009). In zebrafish, Mecp2 is implicated in sensory axon guidance by direct stimulation of transcription of Sema5b and Robo2 (Leong et al. 2015). MECP2 may indirectly regulate signaling by neuronal receptor tyrosine kinases by regulating transcription of protein tyrosine phosphatases, PTPN1 (Krishnan et al. 2015) and PTPN4 (Williamson et al. 2015).<p>MECP2 regulates transcription of several transcription factors involved in functioning of the nervous system, such as CREB1, MEF2C, RBFOX1 (Chahrour et al. 2008) and PPARG (Mann et al. 2010, Joss-Moore et al. 2011).<p>MECP2 associates with transcription and chromatin remodeling factors, such as CREB1 (Chahrour et al. 2008, Chen et al. 2013), the HDAC1/2-containing SIN3A co-repressor complex (Nan et al. 1998), and the NCoR/SMRT complex (Lyst et al. 2013, Ebert et al. 2013). There are contradictory reports on the interaction of MECP2 with the SWI/SNF chromatin-remodeling complex (Harikrishnan et al. 2005, Hu et al. 2006). Interaction of MECP2 with the DNA methyltransferase DNMT1 has been reported, with a concomitant increase in enzymatic activity of DNMT1 (Kimura and Shiota 2003).<p>In addition to DNA binding-dependent regulation of gene expression by MECP2, MECP2 may influence gene expression by interaction with components of the DROSHA microprocessor complex and the consequent change in the levels of mature microRNAs (Cheng et al. 2014, Tsujimura et al. 2015).<p>Increased MECP2 promoter methylation is observed in both male and female autism patients (Nagarajan et al. 2008). Regulatory elements that undergo methylation are found in the promoter and the first intron of MECP2 and their methylation was shown to regulate Mecp2 expression in mice (Liyanage et al. 2013). Mouse Mecp2 promoter methylation was shown to be affected by stress (Franklin et al. 2010).<p>The Rett-like phenotype of Mecp2 null mice is reversible (Guy et al. 2007), but appropriate levels of Mecp2 expression need to be achieved (Alvarez-Saavedra et al. 2007). When Mecp2 expression is restored in astrocytes of Mecp2 null mice, amelioration of Rett symptoms occurs, involving non-cell-autonomous positive effect on mutant neurons and increasing level of the excitatory glutamate transporter VGLUT1 (Lioy et al. 2011). Microglia derived from Mecp2 null mice releases higher than normal levels of glutamate, which has toxic effect on neurons. Increased glutamate secretion may be due to increased levels of glutaminase (Gls), involved in glutamate synthesis, and increased levels of connexin-32 (Gjb1), involved in glutamate release, in Mecp2 null microglia (Maezawa and Jin 2010). Targeted deletion of Mecp2 from Sim1-expressing neurons of the mouse hypothalamus recapitulates some Rett syndrome-like features and highlights the role of Mecp2 in feeding behavior and response to stress (Fyffe et al. 2008).<p>Mecp2 overexpression, similar to MECP2 duplication syndrome, causes neurologic phenotype similar to Rett (Collins et al. 2004, Luikenhuis et al. 2004, Van Esch et al. 2005, Alvarez-Saavedra 2007, Van Esch et al. 2012). The phenotype of the mouse model of the MECP2 duplication syndrome in adult mice is reversible when Mecp2 expression levels are corrected (Sztainberg et al. 2015). View original pathway at:Reactome.</div>

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Reactome Author: Orlic-Milacic, Marija

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  55. Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, Chen WG, Lin Y, Savner E, Griffith EC, Hu L, Steen JA, Weitz CJ, Greenberg ME.; ''Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation.''; PubMed Europe PMC Scholia
  56. Feldman D, Banerjee A, Sur M.; ''Developmental Dynamics of Rett Syndrome.''; PubMed Europe PMC Scholia
  57. Kaddoum L, Panayotis N, Mazarguil H, Giglia-Mari G, Roux JC, Joly E.; ''Isoform-specific anti-MeCP2 antibodies confirm that expression of the e1 isoform strongly predominates in the brain.''; PubMed Europe PMC Scholia
  58. Marcet B, Chevalier B, Luxardi G, Coraux C, Zaragosi LE, Cibois M, Robbe-Sermesant K, Jolly T, Cardinaud B, Moreilhon C, Giovannini-Chami L, Nawrocki-Raby B, Birembaut P, Waldmann R, Kodjabachian L, Barbry P.; ''Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway.''; PubMed Europe PMC Scholia
  59. Sztainberg Y, Chen HM, Swann JW, Hao S, Tang B, Wu Z, Tang J, Wan YW, Liu Z, Rigo F, Zoghbi HY.; ''Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides.''; PubMed Europe PMC Scholia
  60. Krishnan N, Krishnan K, Connors CR, Choy MS, Page R, Peti W, Van Aelst L, Shea SD, Tonks NK.; ''PTP1B inhibition suggests a therapeutic strategy for Rett syndrome.''; PubMed Europe PMC Scholia
  61. Nagarajan RP, Patzel KA, Martin M, Yasui DH, Swanberg SE, Hertz-Picciotto I, Hansen RL, Van de Water J, Pessah IN, Jiang R, Robinson WP, LaSalle JM.; ''MECP2 promoter methylation and X chromosome inactivation in autism.''; PubMed Europe PMC Scholia
  62. Hwang CK, Kim CS, Kim DK, Law PY, Wei LN, Loh HH.; ''Up-regulation of the mu-opioid receptor gene is mediated through chromatin remodeling and transcriptional factors in differentiated neuronal cells.''; PubMed Europe PMC Scholia
  63. Durand S, Patrizi A, Quast KB, Hachigian L, Pavlyuk R, Saxena A, Carninci P, Hensch TK, Fagiolini M.; ''NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2.''; PubMed Europe PMC Scholia
  64. Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D, Rana NA, Pan H, Haltiwanger RS, Bellen HJ.; ''Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling.''; PubMed Europe PMC Scholia
  65. Lyu JW, Yuan B, Cheng TL, Qiu ZL, Zhou WH.; ''Reciprocal regulation of autism-related genes MeCP2 and PTEN via microRNAs.''; PubMed Europe PMC Scholia
  66. Ricciardi S, Boggio EM, Grosso S, Lonetti G, Forlani G, Stefanelli G, Calcagno E, Morello N, Landsberger N, Biffo S, Pizzorusso T, Giustetto M, Broccoli V.; ''Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model.''; PubMed Europe PMC Scholia
  67. Li H, Zhong X, Chau KF, Santistevan NJ, Guo W, Kong G, Li X, Kadakia M, Masliah J, Chi J, Jin P, Zhang J, Zhao X, Chang Q.; ''Cell cycle-linked MeCP2 phosphorylation modulates adult neurogenesis involving the Notch signalling pathway.''; PubMed Europe PMC Scholia
  68. Cheng TL, Wang Z, Liao Q, Zhu Y, Zhou WH, Xu W, Qiu Z.; ''MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex.''; PubMed Europe PMC Scholia
  69. Li W, Pozzo-Miller L.; ''BDNF deregulation in Rett syndrome.''; PubMed Europe PMC Scholia
  70. Bracaglia G, Conca B, Bergo A, Rusconi L, Zhou Z, Greenberg ME, Landsberger N, Soddu S, Kilstrup-Nielsen C.; ''Methyl-CpG-binding protein 2 is phosphorylated by homeodomain-interacting protein kinase 2 and contributes to apoptosis.''; PubMed Europe PMC Scholia
  71. Tao J, Hu K, Chang Q, Wu H, Sherman NE, Martinowich K, Klose RJ, Schanen C, Jaenisch R, Wang W, Sun YE.; ''Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function.''; PubMed Europe PMC Scholia
  72. Liyanage VR, Zachariah RM, Rastegar M.; ''Decitabine alters the expression of Mecp2 isoforms via dynamic DNA methylation at the Mecp2 regulatory elements in neural stem cells.''; PubMed Europe PMC Scholia
  73. Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, Kaspar BK, Hirrlinger PG, Kirchhoff F, Bissonnette JM, Ballas N, Mandel G.; ''A role for glia in the progression of Rett's syndrome.''; PubMed Europe PMC Scholia
  74. Williamson SL, Ellaway CJ, Peters GB, Pelka GJ, Tam PP, Christodoulou J.; ''Deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in twins with a Rett syndrome-like phenotype.''; PubMed Europe PMC Scholia
  75. Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, Israël A.; ''The Notch1 receptor is cleaved constitutively by a furin-like convertase.''; PubMed Europe PMC Scholia
  76. Tsujimura K, Irie K, Nakashima H, Egashira Y, Fukao Y, Fujiwara M, Itoh M, Uesaka M, Imamura T, Nakahata Y, Yamashita Y, Abe T, Takamori S, Nakashima K.; ''miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes.''; PubMed Europe PMC Scholia
  77. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A.; ''Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.''; PubMed Europe PMC Scholia
  78. Franklin TB, Russig H, Weiss IC, Gräff J, Linder N, Michalon A, Vizi S, Mansuy IM.; ''Epigenetic transmission of the impact of early stress across generations.''; PubMed Europe PMC Scholia
  79. Mnatzakanian GN, Lohi H, Munteanu I, Alfred SE, Yamada T, MacLeod PJ, Jones JR, Scherer SW, Schanen NC, Friez MJ, Vincent JB, Minassian BA.; ''A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome.''; PubMed Europe PMC Scholia
  80. Olson CO, Zachariah RM, Ezeonwuka CD, Liyanage VR, Rastegar M.; ''Brain region-specific expression of MeCP2 isoforms correlates with DNA methylation within Mecp2 regulatory elements.''; PubMed Europe PMC Scholia
  81. Ebert DH, Gabel HW, Robinson ND, Kastan NR, Hu LS, Cohen S, Navarro AJ, Lyst MJ, Ekiert R, Bird AP, Greenberg ME.; ''Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR.''; PubMed Europe PMC Scholia
  82. Hu K, Nan X, Bird A, Wang W.; ''Testing for association between MeCP2 and the brahma-associated SWI/SNF chromatin-remodeling complex.''; PubMed Europe PMC Scholia
  83. Su M, Hong J, Zhao Y, Liu S, Xue X.; ''MeCP2 controls hippocampal brain-derived neurotrophic factor expression via homeostatic interactions with microRNA‑132 in rats with depression.''; PubMed Europe PMC Scholia
  84. Livide G, Patriarchi T, Amenduni M, Amabile S, Yasui D, Calcagno E, Lo Rizzo C, De Falco G, Ulivieri C, Ariani F, Mari F, Mencarelli MA, Hell JW, Renieri A, Meloni I.; ''GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells.''; PubMed Europe PMC Scholia
  85. Ji Q, Hao X, Zhang M, Tang W, Yang M, Li L, Xiang D, Desano JT, Bommer GT, Fan D, Fearon ER, Lawrence TS, Xu L.; ''MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.''; PubMed Europe PMC Scholia
  86. Yasui DH, Gonzales ML, Aflatooni JO, Crary FK, Hu DJ, Gavino BJ, Golub MS, Vincent JB, Carolyn Schanen N, Olson CO, Rastegar M, Lasalle JM.; ''Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome.''; PubMed Europe PMC Scholia
  87. Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K, Lugtenberg D, Bienvenu T, Jensen LR, Gecz J, Moraine C, Marynen P, Fryns JP, Froyen G.; ''Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males.''; PubMed Europe PMC Scholia
  88. Fernandez-Valdivia R, Takeuchi H, Samarghandi A, Lopez M, Leonardi J, Haltiwanger RS, Jafar-Nejad H.; ''Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi.''; PubMed Europe PMC Scholia
  89. Li Y, Wang H, Muffat J, Cheng AW, Orlando DA, Lovén J, Kwok SM, Feldman DA, Bateup HS, Gao Q, Hockemeyer D, Mitalipova M, Lewis CA, Vander Heiden MG, Sur M, Young RA, Jaenisch R.; ''Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons.''; PubMed Europe PMC Scholia
  90. Orlic-Milacic M, Kaufman L, Mikhailov A, Cheung AY, Mahmood H, Ellis J, Gianakopoulos PJ, Minassian BA, Vincent JB.; ''Over-expression of either MECP2_e1 or MECP2_e2 in neuronally differentiated cells results in different patterns of gene expression.''; PubMed Europe PMC Scholia
  91. Mann J, Chu DC, Maxwell A, Oakley F, Zhu NL, Tsukamoto H, Mann DA.; ''MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis.''; PubMed Europe PMC Scholia
  92. Cohen B, Bashirullah A, Dagnino L, Campbell C, Fisher WW, Leow CC, Whiting E, Ryan D, Zinyk D, Boulianne G, Hui CC, Gallie B, Phillips RA, Lipshitz HD, Egan SE.; ''Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila.''; PubMed Europe PMC Scholia
  93. Stahl M, Uemura K, Ge C, Shi S, Tashima Y, Stanley P.; ''Roles of Pofut1 and O-fucose in mammalian Notch signaling.''; PubMed Europe PMC Scholia
  94. Gianakopoulos PJ, Zhang Y, Pencea N, Orlic-Milacic M, Mittal K, Windpassinger C, White SJ, Kroisel PM, Chow EW, Saunders CJ, Minassian BA, Vincent JB.; ''Mutations in MECP2 exon 1 in classical Rett patients disrupt MECP2_e1 transcription, but not transcription of MECP2_e2.''; PubMed Europe PMC Scholia
  95. Wang Y, Shao L, Shi S, Harris RJ, Spellman MW, Stanley P, Haltiwanger RS.; ''Modification of epidermal growth factor-like repeats with O-fucose. Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase.''; PubMed Europe PMC Scholia
  96. Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, Neul JL, Gong S, Lu HC, Heintz N, Ekker M, Rubenstein JL, Noebels JL, Rosenmund C, Zoghbi HY.; ''Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.''; PubMed Europe PMC Scholia
  97. Guy J, Gan J, Selfridge J, Cobb S, Bird A.; ''Reversal of neurological defects in a mouse model of Rett syndrome.''; PubMed Europe PMC Scholia
  98. Kerr B, Soto C J, Saez M, Abrams A, Walz K, Young JI.; ''Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes.''; PubMed Europe PMC Scholia
  99. Hashimoto Y, Akiyama Y, Otsubo T, Shimada S, Yuasa Y.; ''Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis.''; PubMed Europe PMC Scholia
  100. He LJ, Liu N, Cheng TL, Chen XJ, Li YD, Shu YS, Qiu ZL, Zhang XH.; ''Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
116657view11:47, 9 May 2021EweitzModified title
114680view16:15, 25 January 2021ReactomeTeamReactome version 75
113127view11:19, 2 November 2020ReactomeTeamReactome version 74
112359view15:28, 9 October 2020ReactomeTeamReactome version 73
102018view15:35, 26 November 2018Marvin M2Ontology Term : 'transcription pathway via transcription factor mediated signaling' added !
101674view13:53, 1 November 2018DeSlOntology Term : 'regulatory pathway' added !
101673view13:52, 1 November 2018DeSlOntology Term : 'Rett syndrome' added !
101654view11:51, 1 November 2018ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
5hmC-DNA R-HSA-9022446 (Reactome)
5hmC-DNAR-HSA-9022446 (Reactome)
5mC-DNA R-HSA-9022447 (Reactome)
5mC-DNAR-HSA-9022447 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AGO2 ProteinQ9UKV8 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
AURKBProteinQ96GD4 (Uniprot-TrEMBL)
Active CaMK IV,(CaMK II)ComplexR-HSA-9007010 (Reactome)
Active PRKACA,CaMK IVComplexR-HSA-9005587 (Reactome)
BDNF gene ProteinENSG00000176697 (Ensembl)
BDNF geneGeneProductENSG00000176697 (Ensembl)
BDNFProteinP23560 (Uniprot-TrEMBL)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
CREB1 gene ProteinENSG00000118260 (Ensembl)
CREB1 geneGeneProductENSG00000118260 (Ensembl)
CREB1ProteinP16220 (Uniprot-TrEMBL)
CRH gene ProteinENSG00000147571 (Ensembl)
CRH geneGeneProductENSG00000147571 (Ensembl)
CRHProteinP06850 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
DGCR8 ProteinQ8WYQ5 (Uniprot-TrEMBL)
DGCR8ProteinQ8WYQ5 (Uniprot-TrEMBL)
DLL1 gene ProteinENSG00000198719 (Ensembl)
DLL1 geneGeneProductENSG00000198719 (Ensembl)
DLL1ProteinO00548 (Uniprot-TrEMBL)
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
FKBP5 gene ProteinENSG00000096060 (Ensembl)
FKBP5 geneGeneProductENSG00000096060 (Ensembl)
FKBP5ProteinQ13451 (Uniprot-TrEMBL)
FOXG1 ProteinP55316 (Uniprot-TrEMBL)
FOXG1ProteinP55316 (Uniprot-TrEMBL)
GAD1 gene ProteinENSG00000128683 (Ensembl)
GAD1 geneGeneProductENSG00000128683 (Ensembl)
GAD1ProteinQ99259 (Uniprot-TrEMBL)
GAD2 gene ProteinENSG00000136750 (Ensembl)
GAD2 geneGeneProductENSG00000136750 (Ensembl)
GAD2ProteinQ05329 (Uniprot-TrEMBL) GAD65 or GAD2 is concentrated in the nerve terminal region in the neurons and is involved in the synthesis of GABA which is used as a neurotransmitter.
GAMT gene ProteinENSG00000130005 (Ensembl)
GAMT geneGeneProductENSG00000130005 (Ensembl)
GAMTProteinQ14353 (Uniprot-TrEMBL)
GPRIN1 gene ProteinENSG00000169258 (Ensembl)
GPRIN1 geneGeneProductENSG00000169258 (Ensembl)
GPRIN1ProteinQ7Z2K8 (Uniprot-TrEMBL)
GPS2 ProteinQ13227 (Uniprot-TrEMBL)
GRIA2 gene ProteinENSG00000120251 (Ensembl)
GRIA2 geneGeneProductENSG00000120251 (Ensembl)
GRIA2ProteinP42262 (Uniprot-TrEMBL)
GRIN2A gene ProteinENSG00000183454 (Ensembl)
GRIN2A geneGeneProductENSG00000183454 (Ensembl)
GRIN2AProteinQ12879 (Uniprot-TrEMBL)
GRIN2B gene ProteinENSG00000273079 (Ensembl)
GRIN2B geneGeneProductENSG00000273079 (Ensembl)
GRIN2BProteinQ13224 (Uniprot-TrEMBL)
HDAC1 ProteinQ13547 (Uniprot-TrEMBL)
HDAC2 ProteinQ92769 (Uniprot-TrEMBL)
HDAC3 ProteinO15379 (Uniprot-TrEMBL)
HIPK2ProteinQ9H2X6 (Uniprot-TrEMBL)
HTT ProteinP42858 (Uniprot-TrEMBL)
HTTProteinP42858 (Uniprot-TrEMBL)
IRAK1 gene ProteinENSG00000184216 (Ensembl)
IRAK1 geneGeneProductENSG00000184216 (Ensembl)
IRAK1ProteinP51617 (Uniprot-TrEMBL)
LBR ProteinQ14739 (Uniprot-TrEMBL)
LBRProteinQ14739 (Uniprot-TrEMBL)
MECP2 mRNA:miR-132 RISCComplexR-HSA-9021180 (Reactome)
MECP2 mRNAComplexR-HSA-9021217 (Reactome)
MECP2:5hmC-DNAComplexR-HSA-9022466 (Reactome)
MECP2:5mC-DNAComplexR-HSA-9022463 (Reactome)
MECP2:CREB1 geneComplexR-HSA-9021865 (Reactome)
MECP2:CRH geneComplexR-HSA-9017996 (Reactome)
MECP2:DGCR8ComplexR-HSA-9022340 (Reactome)
MECP2:DLL1 geneComplexR-HSA-9023387 (Reactome)
MECP2:FKBP5 geneComplexR-HSA-9022756 (Reactome)
MECP2:FOXG1ComplexR-HSA-9022636 (Reactome)
MECP2:GAD1 geneComplexR-HSA-9022984 (Reactome)
MECP2:GAD2 geneComplexR-HSA-9022982 (Reactome)
MECP2:GAMT geneComplexR-HSA-9022024 (Reactome)
MECP2:GPRIN1 geneComplexR-HSA-9022056 (Reactome)
MECP2:GRIN2A geneComplexR-HSA-9006547 (Reactome)
MECP2:GRIN2B geneComplexR-HSA-9020506 (Reactome)
MECP2:HTTComplexR-HSA-9023598 (Reactome)
MECP2:IRAK1 geneComplexR-HSA-9615814 (Reactome)
MECP2:LBRComplexR-HSA-9018599 (Reactome)
MECP2:MEF2C geneComplexR-HSA-9022092 (Reactome)
MECP2:MET geneComplexR-HSA-9005533 (Reactome)
MECP2:MOBP geneComplexR-HSA-9022904 (Reactome)
MECP2:NCoR/SMRT complexComplexR-HSA-9005564 (Reactome)
MECP2:NOTCH1 geneComplexR-HSA-9023372 (Reactome)
MECP2:OPRK1 geneComplexR-HSA-9021993 (Reactome)
MECP2:PPARG geneComplexR-HSA-9017458 (Reactome)
MECP2:PTPN1 geneComplexR-HSA-9023531 (Reactome)
MECP2:PTPN4 geneComplexR-HSA-9006834 (Reactome)
MECP2:PVALB geneComplexR-HSA-9006521 (Reactome)
MECP2:RBFOX1 geneComplexR-HSA-9022121 (Reactome)
MECP2:SGK1 geneComplexR-HSA-9022789 (Reactome)
MECP2:SIN3A:HDAC1,HDAC2ComplexR-HSA-9022422 (Reactome)
MECP2:SIN3A:HDAC1:BDNF geneComplexR-HSA-9006120 (Reactome)
MECP2:SIN3A:HDAC1:HDAC1:OPRM1 geneComplexR-HSA-9017956 (Reactome)
MECP2:SIN3A:HDAC1:HDAC2:GRIA2 geneComplexR-HSA-9022393 (Reactome)
MECP2:SIN3A:HDAC1:HDAC2ComplexR-HSA-9005990 (Reactome)
MECP2:SIN3A:HDAC1ComplexR-HSA-9022425 (Reactome)
MECP2:SOX2:MIR137 geneComplexR-HSA-9615538 (Reactome)
MECP2:TRPC3 geneComplexR-HSA-9006010 (Reactome)
MECP2:p-S133-CREB1:SLC2A3 geneComplexR-HSA-9022198 (Reactome)
MECP2:p-S133-CREB1:SST geneComplexR-HSA-9021924 (Reactome)
MECP2:p-S133-CREB1ComplexR-HSA-9021896 (Reactome)
MECP2ComplexR-HSA-9005549 (Reactome)
MECP2_e1 ProteinP51608-2 (Uniprot-TrEMBL)
MECP2_e1 mRNA ProteinENST00000453960 (Ensembl)
MECP2_e2 ProteinP51608-1 (Uniprot-TrEMBL)
MECP2_e2 mRNA ProteinENST00000303391 (Ensembl)
MEF2C gene ProteinENSG00000081189 (Ensembl)
MEF2C geneGeneProductENSG00000081189 (Ensembl)
MEF2CProteinQ06413 (Uniprot-TrEMBL)
MET gene ProteinENSG00000105976 (Ensembl)
MET geneGeneProductENSG00000105976 (Ensembl)
METProteinP08581 (Uniprot-TrEMBL)
MIR132 gene ProteinENSG00000267200 (Ensembl)
MIR132 geneGeneProductENSG00000267200 (Ensembl)
MIR137 gene ProteinENSG00000284202 (Ensembl)
MIR137 geneGeneProductENSG00000284202 (Ensembl)
MOBP gene ProteinENSG00000168314 (Ensembl)
MOBP geneGeneProductENSG00000168314 (Ensembl)
MOBPProteinQ13875 (Uniprot-TrEMBL)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
NCOR1 ProteinO75376 (Uniprot-TrEMBL)
NCOR2 ProteinQ9Y618 (Uniprot-TrEMBL)
NCoR/SMRT complexComplexR-HSA-9005706 (Reactome)
NOTCH1 gene ProteinENSG00000148400 (Ensembl)
NOTCH1 geneGeneProductENSG00000148400 (Ensembl)
NOTCH1 mRNARnaENST00000277541 (Ensembl)
OPRK1 gene ProteinENSG00000082556 (Ensembl)
OPRK1 geneGeneProductENSG00000082556 (Ensembl)
OPRK1ProteinP41145 (Uniprot-TrEMBL)
OPRM1 gene ProteinENSG00000112038 (Ensembl)
OPRM1 geneGeneProductENSG00000112038 (Ensembl)
OPRM1ProteinP35372 (Uniprot-TrEMBL)
PPARG gene ProteinENSG00000132170 (Ensembl)
PPARG geneGeneProductENSG00000132170 (Ensembl)
PPARGProteinP37231 (Uniprot-TrEMBL)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PTEN mRNA ProteinENST00000371953 (Ensembl)
PTEN mRNA:miR-137 RISCComplexR-HSA-9615784 (Reactome)
PTEN mRNARnaENST00000371953 (Ensembl)
PTENProteinP60484 (Uniprot-TrEMBL)
PTPN1 gene ProteinENSG00000196396 (Ensembl)
PTPN1 geneGeneProductENSG00000196396 (Ensembl)
PTPN1ProteinP18031 (Uniprot-TrEMBL)
PTPN4 gene ProteinENSG00000088179 (Ensembl)
PTPN4 geneGeneProductENSG00000088179 (Ensembl)
PTPN4ProteinP29074 (Uniprot-TrEMBL)
PVALB gene ProteinENSG00000100362 (Ensembl)
PVALB geneGeneProductENSG00000100362 (Ensembl)
PVALBProteinP20472 (Uniprot-TrEMBL)
Pre-NOTCH Expression and ProcessingPathwayR-HSA-1912422 (Reactome) In humans and other mammals the NOTCH gene family has four members, NOTCH1, NOTCH2, NOTCH3 and NOTCH4, encoded on four different chromosomes. Their transcription is developmentally regulated and tissue specific, but very little information exists on molecular mechanisms of transcriptional regulation. Translation of NOTCH mRNAs is negatively regulated by a number of recently discovered microRNAs (Li et al. 2009, Pang et al.2010, Ji et al. 2009, Kong et al. 2010, Marcet et al. 2011, Ghisi et al. 2011, Song et al. 2009, Hashimoto et al. 2010, Costa et al. 2009).

The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011).

In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling.
RBFOX1 gene ProteinENSG00000078328 (Ensembl)
RBFOX1 geneGeneProductENSG00000078328 (Ensembl)
RBFOX1ProteinQ9NWB1 (Uniprot-TrEMBL)
SGK1 gene ProteinENSG00000118515 (Ensembl)
SGK1 geneGeneProductENSG00000118515 (Ensembl)
SGK1ProteinO00141 (Uniprot-TrEMBL)
SIN3A ProteinQ96ST3 (Uniprot-TrEMBL)
SIN3A:HDAC1,HDAC2 dimersComplexR-HSA-9022431 (Reactome)
SLC2A3 gene ProteinENSG00000059804 (Ensembl)
SLC2A3 geneGeneProductENSG00000059804 (Ensembl)
SLC2A3ProteinP11169 (Uniprot-TrEMBL)
SOX2 ProteinP48431 (Uniprot-TrEMBL)
SOX2ProteinP48431 (Uniprot-TrEMBL)
SST gene ProteinENSG00000157005 (Ensembl)
SST geneGeneProductENSG00000157005 (Ensembl)
SST(103-116) ProteinP61278 (Uniprot-TrEMBL)
SST(89-116) ProteinP61278 (Uniprot-TrEMBL)
Signaling by NOTCHPathwayR-HSA-157118 (Reactome) The Notch Signaling Pathway (NSP) is a highly conserved pathway for cell-cell communication. NSP is involved in the regulation of cellular differentiation, proliferation, and specification. For example, it is utilised by continually renewing adult tissues such as blood, skin, and gut epithelium not only to maintain stem cells in a proliferative, pluripotent, and undifferentiated state but also to direct the cellular progeny to adopt different developmental cell fates. Analogously, it is used during embryonic development to create fine-grained patterns of differentiated cells, notably during neurogenesis where the NSP controls patches such as that of the vertebrate inner ear where individual hair cells are surrounded by supporting cells.
This process is known as lateral inhibition: a molecular mechanism whereby individual cells within a field are stochastically selected to adopt particular cell fates and the NSP inhibits their direct neighbours from doing the same. The NSP has been adopted by several other biological systems for binary cell fate choice. In addition, the NSP is also used during vertebrate segmentation to divide the growing embryo into regular blocks called somites which eventually form the vertebrae. The core of this process relies on regular pulses of Notch signaling generated from a molecular oscillator in the presomatic mesoderm.
The Notch receptor is synthesized in the rough endoplasmic reticulum as a single polypeptide precursor. Newly synthesized Notch receptor is proteolytically cleaved in the trans-golgi network, creating a heterodimeric mature receptor comprising of non-covalently associated extracellular and transmembrane subunits. This assembly travels to the cell surface ready to interact with specific ligands. Following ligand activation and further proteolytic cleavage, an intracellular domain is released and translocates to the nucleus where it regulates gene expression.
SomatostatinComplexR-HSA-374714 (Reactome)
TBL1X ProteinO60907 (Uniprot-TrEMBL)
TBL1XR1 ProteinQ9BZK7 (Uniprot-TrEMBL)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
TRPC3 gene ProteinENSG00000138741 (Ensembl)
TRPC3 geneGeneProductENSG00000138741 (Ensembl)
TRPC3(1-848)ProteinQ13507 (Uniprot-TrEMBL)
miR-132 RISCComplexR-HSA-9021177 (Reactome)
miR-132-5p ProteinMI0000449 (miRBase mature sequence)
miR-137 ProteinMI0000454 (miRBase mature sequence)
miR-137 RISCComplexR-HSA-9615669 (Reactome)
p-S133-CREB1 homodimerComplexR-HSA-111911 (Reactome)
p-S133-CREB1 ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB1:MIR132 geneComplexR-HSA-9615489 (Reactome)
p-S423-MECP2ComplexR-HSA-9007002 (Reactome)
p-S423-MECP2_e2 ProteinP51608-1 (Uniprot-TrEMBL)
p-S435-MECP2_e1 ProteinP51608-2 (Uniprot-TrEMBL)
p-S80-MECP2ComplexR-HSA-9022332 (Reactome)
p-S80-MECP2_e2 ProteinP51608-1 (Uniprot-TrEMBL)
p-S92-MECP2_e1 ProteinP51608-2 (Uniprot-TrEMBL)
p-T286-CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
p-T287-CAMK2B ProteinQ13554 (Uniprot-TrEMBL)
p-T287-CAMK2D ProteinQ13557 (Uniprot-TrEMBL)
p-T287-CAMK2G ProteinQ13555 (Uniprot-TrEMBL)
p-T308-MECP2ComplexR-HSA-9005562 (Reactome)
p-T308-MECP2_e2 ProteinP51608-1 (Uniprot-TrEMBL)
p-T320-MeCP2_e1 ProteinP51608-2 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
5hmC-DNAR-HSA-9022453 (Reactome)
5mC-DNAR-HSA-9022456 (Reactome)
ADPArrowR-HSA-8986937 (Reactome)
ADPArrowR-HSA-9006992 (Reactome)
ADPArrowR-HSA-9022314 (Reactome)
ADPArrowR-HSA-9023132 (Reactome)
ATPR-HSA-8986937 (Reactome)
ATPR-HSA-9006992 (Reactome)
ATPR-HSA-9022314 (Reactome)
ATPR-HSA-9023132 (Reactome)
AURKBmim-catalysisR-HSA-9023132 (Reactome)
Active CaMK IV,(CaMK II)mim-catalysisR-HSA-9006992 (Reactome)
Active PRKACA,CaMK IVTBarR-HSA-8986939 (Reactome)
Active PRKACA,CaMK IVmim-catalysisR-HSA-8986937 (Reactome)
BDNF geneR-HSA-9006050 (Reactome)
BDNF geneR-HSA-9006122 (Reactome)
BDNFArrowR-HSA-9006122 (Reactome)
CREB1 geneR-HSA-9021847 (Reactome)
CREB1 geneR-HSA-9021851 (Reactome)
CREB1ArrowR-HSA-9021847 (Reactome)
CRH geneR-HSA-9017983 (Reactome)
CRH geneR-HSA-9017988 (Reactome)
CRHArrowR-HSA-9017988 (Reactome)
DGCR8R-HSA-9022315 (Reactome)
DLL1 geneR-HSA-9023348 (Reactome)
DLL1 geneR-HSA-9023351 (Reactome)
DLL1ArrowR-HSA-9023351 (Reactome)
FKBP5 geneR-HSA-9022728 (Reactome)
FKBP5 geneR-HSA-9022734 (Reactome)
FKBP5ArrowR-HSA-9022728 (Reactome)
FOXG1R-HSA-9022625 (Reactome)
GAD1 geneR-HSA-9022934 (Reactome)
GAD1 geneR-HSA-9022935 (Reactome)
GAD1ArrowR-HSA-9022934 (Reactome)
GAD2 geneR-HSA-9022941 (Reactome)
GAD2 geneR-HSA-9022942 (Reactome)
GAD2ArrowR-HSA-9022942 (Reactome)
GAMT geneR-HSA-9021945 (Reactome)
GAMT geneR-HSA-9021953 (Reactome)
GAMTArrowR-HSA-9021953 (Reactome)
GPRIN1 geneR-HSA-9021946 (Reactome)
GPRIN1 geneR-HSA-9021948 (Reactome)
GPRIN1ArrowR-HSA-9021948 (Reactome)
GRIA2 geneR-HSA-9022359 (Reactome)
GRIA2 geneR-HSA-9022365 (Reactome)
GRIA2ArrowR-HSA-9022365 (Reactome)
GRIN2A geneR-HSA-9006490 (Reactome)
GRIN2A geneR-HSA-9006507 (Reactome)
GRIN2AArrowR-HSA-9006507 (Reactome)
GRIN2B geneR-HSA-9020504 (Reactome)
GRIN2B geneR-HSA-9020513 (Reactome)
GRIN2BArrowR-HSA-9020513 (Reactome)
HIPK2mim-catalysisR-HSA-9022314 (Reactome)
HTTR-HSA-9023592 (Reactome)
IRAK1 geneR-HSA-9615801 (Reactome)
IRAK1 geneR-HSA-9615829 (Reactome)
IRAK1ArrowR-HSA-9615829 (Reactome)
LBRR-HSA-9018594 (Reactome)
MECP2 mRNA:miR-132 RISCArrowR-HSA-9021182 (Reactome)
MECP2 mRNA:miR-132 RISCTBarR-HSA-9021183 (Reactome)
MECP2 mRNAR-HSA-9021182 (Reactome)
MECP2 mRNAR-HSA-9021183 (Reactome)
MECP2:5hmC-DNAArrowR-HSA-9022453 (Reactome)
MECP2:5mC-DNAArrowR-HSA-9022456 (Reactome)
MECP2:CREB1 geneArrowR-HSA-9021847 (Reactome)
MECP2:CREB1 geneArrowR-HSA-9021851 (Reactome)
MECP2:CRH geneArrowR-HSA-9017983 (Reactome)
MECP2:CRH geneTBarR-HSA-9017988 (Reactome)
MECP2:DGCR8ArrowR-HSA-9022315 (Reactome)
MECP2:DLL1 geneArrowR-HSA-9023348 (Reactome)
MECP2:DLL1 geneTBarR-HSA-9023351 (Reactome)
MECP2:FKBP5 geneArrowR-HSA-9022734 (Reactome)
MECP2:FKBP5 geneTBarR-HSA-9022728 (Reactome)
MECP2:FOXG1ArrowR-HSA-9022625 (Reactome)
MECP2:GAD1 geneArrowR-HSA-9022934 (Reactome)
MECP2:GAD1 geneArrowR-HSA-9022935 (Reactome)
MECP2:GAD2 geneArrowR-HSA-9022941 (Reactome)
MECP2:GAD2 geneArrowR-HSA-9022942 (Reactome)
MECP2:GAMT geneArrowR-HSA-9021945 (Reactome)
MECP2:GAMT geneArrowR-HSA-9021953 (Reactome)
MECP2:GPRIN1 geneArrowR-HSA-9021946 (Reactome)
MECP2:GPRIN1 geneArrowR-HSA-9021948 (Reactome)
MECP2:GRIN2A geneArrowR-HSA-9006490 (Reactome)
MECP2:GRIN2A geneArrowR-HSA-9006507 (Reactome)
MECP2:GRIN2B geneArrowR-HSA-9020504 (Reactome)
MECP2:GRIN2B geneTBarR-HSA-9020513 (Reactome)
MECP2:HTTArrowR-HSA-9023592 (Reactome)
MECP2:IRAK1 geneArrowR-HSA-9615801 (Reactome)
MECP2:IRAK1 geneTBarR-HSA-9615829 (Reactome)
MECP2:LBRArrowR-HSA-9018594 (Reactome)
MECP2:MEF2C geneArrowR-HSA-9021950 (Reactome)
MECP2:MEF2C geneTBarR-HSA-9021949 (Reactome)
MECP2:MET geneArrowR-HSA-8986940 (Reactome)
MECP2:MET geneArrowR-HSA-8986943 (Reactome)
MECP2:MOBP geneArrowR-HSA-9022872 (Reactome)
MECP2:MOBP geneTBarR-HSA-9022870 (Reactome)
MECP2:NCoR/SMRT complexArrowR-HSA-8986939 (Reactome)
MECP2:NOTCH1 geneArrowR-HSA-9023346 (Reactome)
MECP2:NOTCH1 geneTBarR-HSA-9023345 (Reactome)
MECP2:OPRK1 geneArrowR-HSA-9021951 (Reactome)
MECP2:OPRK1 geneArrowR-HSA-9021954 (Reactome)
MECP2:PPARG geneArrowR-HSA-9017447 (Reactome)
MECP2:PPARG geneTBarR-HSA-9017441 (Reactome)
MECP2:PTPN1 geneArrowR-HSA-9023538 (Reactome)
MECP2:PTPN1 geneTBarR-HSA-9023549 (Reactome)
MECP2:PTPN4 geneArrowR-HSA-9006585 (Reactome)
MECP2:PTPN4 geneArrowR-HSA-9006588 (Reactome)
MECP2:PVALB geneArrowR-HSA-9006503 (Reactome)
MECP2:PVALB geneTBarR-HSA-9006508 (Reactome)
MECP2:RBFOX1 geneArrowR-HSA-9021944 (Reactome)
MECP2:RBFOX1 geneTBarR-HSA-9021952 (Reactome)
MECP2:SGK1 geneArrowR-HSA-9022770 (Reactome)
MECP2:SGK1 geneTBarR-HSA-9022764 (Reactome)
MECP2:SIN3A:HDAC1,HDAC2ArrowR-HSA-9005995 (Reactome)
MECP2:SIN3A:HDAC1:BDNF geneArrowR-HSA-9006050 (Reactome)
MECP2:SIN3A:HDAC1:BDNF geneTBarR-HSA-9006122 (Reactome)
MECP2:SIN3A:HDAC1:HDAC1:OPRM1 geneArrowR-HSA-9017954 (Reactome)
MECP2:SIN3A:HDAC1:HDAC1:OPRM1 geneTBarR-HSA-9017921 (Reactome)
MECP2:SIN3A:HDAC1:HDAC2:GRIA2 geneArrowR-HSA-9022359 (Reactome)
MECP2:SIN3A:HDAC1:HDAC2:GRIA2 geneTBarR-HSA-9022365 (Reactome)
MECP2:SIN3A:HDAC1:HDAC2R-HSA-9017954 (Reactome)
MECP2:SIN3A:HDAC1:HDAC2R-HSA-9022359 (Reactome)
MECP2:SIN3A:HDAC1R-HSA-9006050 (Reactome)
MECP2:SOX2:MIR137 geneArrowR-HSA-9615536 (Reactome)
MECP2:SOX2:MIR137 geneTBarR-HSA-9615554 (Reactome)
MECP2:TRPC3 geneArrowR-HSA-9005988 (Reactome)
MECP2:TRPC3 geneArrowR-HSA-9005994 (Reactome)
MECP2:p-S133-CREB1:SLC2A3 geneArrowR-HSA-9022175 (Reactome)
MECP2:p-S133-CREB1:SLC2A3 geneArrowR-HSA-9022186 (Reactome)
MECP2:p-S133-CREB1:SST geneArrowR-HSA-9021919 (Reactome)
MECP2:p-S133-CREB1:SST geneArrowR-HSA-9021935 (Reactome)
MECP2:p-S133-CREB1ArrowR-HSA-9021888 (Reactome)
MECP2:p-S133-CREB1R-HSA-9021919 (Reactome)
MECP2:p-S133-CREB1R-HSA-9022175 (Reactome)
MECP2ArrowR-HSA-9006122 (Reactome)
MECP2ArrowR-HSA-9021183 (Reactome)
MECP2R-HSA-8986937 (Reactome)
MECP2R-HSA-8986939 (Reactome)
MECP2R-HSA-8986943 (Reactome)
MECP2R-HSA-9005988 (Reactome)
MECP2R-HSA-9005995 (Reactome)
MECP2R-HSA-9006490 (Reactome)
MECP2R-HSA-9006503 (Reactome)
MECP2R-HSA-9006588 (Reactome)
MECP2R-HSA-9006992 (Reactome)
MECP2R-HSA-9017447 (Reactome)
MECP2R-HSA-9017983 (Reactome)
MECP2R-HSA-9018594 (Reactome)
MECP2R-HSA-9020504 (Reactome)
MECP2R-HSA-9021851 (Reactome)
MECP2R-HSA-9021888 (Reactome)
MECP2R-HSA-9021944 (Reactome)
MECP2R-HSA-9021945 (Reactome)
MECP2R-HSA-9021946 (Reactome)
MECP2R-HSA-9021950 (Reactome)
MECP2R-HSA-9021954 (Reactome)
MECP2R-HSA-9022314 (Reactome)
MECP2R-HSA-9022453 (Reactome)
MECP2R-HSA-9022456 (Reactome)
MECP2R-HSA-9022625 (Reactome)
MECP2R-HSA-9022734 (Reactome)
MECP2R-HSA-9022770 (Reactome)
MECP2R-HSA-9022872 (Reactome)
MECP2R-HSA-9022935 (Reactome)
MECP2R-HSA-9022941 (Reactome)
MECP2R-HSA-9023132 (Reactome)
MECP2R-HSA-9023346 (Reactome)
MECP2R-HSA-9023348 (Reactome)
MECP2R-HSA-9023538 (Reactome)
MECP2R-HSA-9023592 (Reactome)
MECP2R-HSA-9615536 (Reactome)
MECP2R-HSA-9615801 (Reactome)
MEF2C geneR-HSA-9021949 (Reactome)
MEF2C geneR-HSA-9021950 (Reactome)
MEF2CArrowR-HSA-9021949 (Reactome)
MET geneR-HSA-8986940 (Reactome)
MET geneR-HSA-8986943 (Reactome)
METArrowR-HSA-8986940 (Reactome)
MIR132 geneR-HSA-9615490 (Reactome)
MIR132 geneR-HSA-9615501 (Reactome)
MIR137 geneR-HSA-9615536 (Reactome)
MIR137 geneR-HSA-9615554 (Reactome)
MOBP geneR-HSA-9022870 (Reactome)
MOBP geneR-HSA-9022872 (Reactome)
MOBPArrowR-HSA-9022870 (Reactome)
NCoR/SMRT complexR-HSA-8986939 (Reactome)
NOTCH1 geneR-HSA-9023345 (Reactome)
NOTCH1 geneR-HSA-9023346 (Reactome)
NOTCH1 mRNAArrowR-HSA-9023345 (Reactome)
OPRK1 geneR-HSA-9021951 (Reactome)
OPRK1 geneR-HSA-9021954 (Reactome)
OPRK1ArrowR-HSA-9021951 (Reactome)
OPRM1 geneR-HSA-9017921 (Reactome)
OPRM1 geneR-HSA-9017954 (Reactome)
OPRM1ArrowR-HSA-9017921 (Reactome)
PPARG geneR-HSA-9017441 (Reactome)
PPARG geneR-HSA-9017447 (Reactome)
PPARGArrowR-HSA-9017441 (Reactome)
PTEN mRNA:miR-137 RISCArrowR-HSA-9615570 (Reactome)
PTEN mRNA:miR-137 RISCTBarR-HSA-9615571 (Reactome)
PTEN mRNAR-HSA-9615570 (Reactome)
PTEN mRNAR-HSA-9615571 (Reactome)
PTENArrowR-HSA-9615571 (Reactome)
PTPN1 geneR-HSA-9023538 (Reactome)
PTPN1 geneR-HSA-9023549 (Reactome)
PTPN1ArrowR-HSA-9023549 (Reactome)
PTPN4 geneR-HSA-9006585 (Reactome)
PTPN4 geneR-HSA-9006588 (Reactome)
PTPN4ArrowR-HSA-9006585 (Reactome)
PVALB geneR-HSA-9006503 (Reactome)
PVALB geneR-HSA-9006508 (Reactome)
PVALBArrowR-HSA-9006508 (Reactome)
R-HSA-8986937 (Reactome) Calcium-dependent protein kinases, PKA and CaMK IV, activated by neuronal membrane depolarization, phosphorylate MECP2 at threonine residue T308. Only the PKA C-alpha isoform (PRKACA) was experimentally tested. T308 corresponds to T320 in the longer MECP2 splicing isoform, MECP2_e1 (MECP2B). Phosphorylation of MECP2 at threonine residue T308 is correlated with neuronal activity and inhibits binding of MECP2 to the nuclear receptor co-repressor complex (NCoR/SMRT) (Ebert et al. 2013).
R-HSA-8986939 (Reactome) MECP2 binds the nuclear receptor co-repressor complex (NCoR/SMRT). This interaction is inhibited by MECP2 phosphorylation at threonine residue T308. The following NCoR/SMRT complex components were co-immunoprecipitated with MECP2: NCOR1, NCOR2, HDAC3, TBL1 (TBL1X), TBLR1 (TBL1XR1) and GPS2 (Lyst et al. 2013, Ebert et al. 2013). Direct interaction was confirmed between the transcriptional repressor domain of MECP2 and NCOR1, NCOR2, TBL1X and TBLR1 (Lyst et al. 2013). NCoR/SMRT complex consists of either NCOR1 (NCoR) or NCOR2 (SMRT), GPS2, HDAC3 and tetramers of either TBL1X or TBL1XR1 (Oberoi et al. 2011, reviewed by Watson et al. 2012).
R-HSA-8986940 (Reactome) MECP2 directly stimulates transcription of the MET gene, encoding MET receptor tyrosine kinase. MET promoter SNV rs1858830 C 'low activity' allele is associated with low expression of MET in autism spectrum disorders (ASD). Although this MET promoter SNV overlaps with the MECP2 binding site, presence of the low activity allele does not inhibit MECP2-mediated stimulation of MET transcription. Mutant MECP2 proteins associated with Rett syndrome show reduced transactivation of the MET gene. MET expression is significantly decreased in the temporal cortex of female Rett patients (Plummer et al. 2013).
R-HSA-8986943 (Reactome) MECP2 binds the promoter of the MET gene, encoding receptor tyrosine kinase MET. The MECP2 binding site in the MET promoter contains the SNV sequence whose rs1858830 C 'low activity' allele is associated with an increased risk for autism spectrum disorders (ASD) (Plummer et al. 2013).
R-HSA-9005988 (Reactome) MECP2 binds to the TRPC3 gene, a couple of kilobases upstream of the transcription start site (Li et al. 2012).
R-HSA-9005994 (Reactome) Binding of MECP2 to the TRPC3 gene stimulates transcription of TRPC3, which encodes a BDNF-responsive transient receptor potential canonical channel (Li et al. 2012).
R-HSA-9005995 (Reactome) MECP2 binds the SIN3A co-repressor complex. This interaction involves the transcriptional repressor domain of MECP2 and the amino-terminal part of the HDAC-interaction domain (HID) of SIN3A. HDAC1 and HDAC2 are part of the SIN3A co-repressor complex that co-immunoprecipitates with MECP2. Presence of other components of the SIN3A co-repressor complex has not been tested (Nan et al. 1998). MECP2 is not an obligate component of the SIN3A corepressor complex (Klose et al. 2004).
R-HSA-9006050 (Reactome) Based on studies in mice, the complex of MECP2, SIN3A and HDAC1 binds one of several alternative promoters of the brain-derived neurotrophic factor (BDNF) gene, the promoter in front of the BDNF exon IV (Martinowich et al. 2003). This promoter is homologous to the promoter in front of the rat Bdnf exon III, which was also shown to be occupied by Mecp2 (Chen et al. 2003).
R-HSA-9006122 (Reactome) Binding of MECP2 to the promoter of the BDNF gene represses BDNF transcription in unstimulated neurons, tying BDNF expression with neuronal membrane depolarization (Chen et al. 2003, Martinowich et al. 2003). BDNF encodes Brain-derived neurotrophic factor. MECP2-mediated recruitment of the histone deacetylase (HDAC) containing SIN3A co-repressor complex is thought to induce histone deacetylation at the BDNF promoter, invoking BDNF gene silencing (Martinowich et al. 2003).

Surprisingly, MECP2 deficiency in Rett syndrome results in an overall decreased expression of BDNF (Klein et al. 2007, Chahrour et al. 2008, Fyffe et al. 2008). One proposed mechanism is indirect, through the loss of MECP2-mediated repression of REST and RCOR1 (CoREST) genes, as REST and RCOR1 act as repressors of BDNF transcription from promoter 1 (Abuhatzira et al. 2007). Previously, it was reported that the CoREST complex also represses transcription of Bdnf from the Mecp2-binding murine promoter 4 (corresponding to human MECP2-binding BDNF promoter 3) (Ballas et al. 2005).

For detailed review of dual regulation of BDNF transcription by MECP2, please refer to Li and Pozzo-Miller 2014, and KhorashidAhmad et al. 2016.

Deficit in Bdnf expression in Mecp2 null mice results in downregulation of Igf1 expression through a microRNA-dependent pathway regulated by Bdnf signaling. Induction of signaling by the beta2-adrenegic receptor can restore Igf1 expression in Mecp2 null mice (Mellios et al. 2014).

R-HSA-9006490 (Reactome) Based on studies in mice, MECP2 binds to the promoter of the GRIN2A gene, encoding NMDA receptor 2A (Durand et al. 2012).
R-HSA-9006503 (Reactome) Based on studies in mice, MECP2 binds the promoter of the PVALB gene, encoding parvalbumin alpha (Durand et al. 2012).
R-HSA-9006507 (Reactome) Based on studies in mice, MECP2 stimulates transcription of the GRIN2A gene, encoding NMDA receptor 2A (Durand et al. 2012).
R-HSA-9006508 (Reactome) Based on studies in mice, binding of MECP2 to the promoter of the PVALB gene represses PVALB transcription. Pvalb levels are increased in visual cortical neurons of Mecp2 knockout mice, which is thought to contribute to visual regression (Durand et al. 2012).
R-HSA-9006585 (Reactome) Binding of MECP2 to the PTPN4 gene promoter stimulates PTPN4 transcription. PTPN4 gene encodes a protein tyrosine phosphatase, non-receptor type, also known as MEG, PTPase-MEG1 or PTPMEG. Expression of Ptpn4 is reduced in Mecp2 null mice used as a Rett syndrome model. A hemizygous PTPN4 gene deletion was found in twins with a Rett-like phenotype (Williamson et al. 2015).
R-HSA-9006588 (Reactome) MECP2 binds to the promoter of the PTPN4 gene, encoding protein tyrosine phosphatase, non-receptor type 4, also known as MEG, PTPase-MEG1 or PTPMEG (Wiliamson et al. 2015).
R-HSA-9006992 (Reactome) In resting neurons, MECP2 is phosphorylated at serine residue S80, which results in a decreased association of MECP2 with chromatin. In activity-induced neurons, upon neuronal membrane depolarization, MECP2 S80 becomes dephosphorylated, and MECP2 acquires phosphorylation on serine S423 (corresponding to mouse Mecp2 serine S421). CaMK IV is one of the kinases that can phosphorylate MECP2 on S423. Phosphorylation of MECP2 at S423 increases MECP2 binding to chromatin (Zhou et al. 2006, Tao et al. 2009, Qiu et al. 2012).
R-HSA-9017441 (Reactome) Based on studies in mouse hepatocytes (Mann et al. 2011) and rat lung cells (Joss-Moore et al. 2011), transcription of the PPARG gene is inhibited by binding of MECP2 to PPARG promoter. Binding of MECP2 to the PPAR gene correlates with the appearance of repressive methylation marks on histones associated with the PPARG promoter (Mann et al. 2010).
R-HSA-9017447 (Reactome) Based on studies in mouse hepatocytes (Mann et al. 2010) and rat lung cells (Joss-Moore et al. 2014), MECP2 binds to the promoter region of the PPARG gene, encoding a nuclear receptor PPAR-gamma.
R-HSA-9017921 (Reactome) Based on studies in mice, association of MECP2 with the hypermethylated OPRM1 gene promoter, encoding Mu-type opioid receptor (MOR), correlates with transcriptional repression of OPRM1 in the cerebellum. MECP2-mediated transcriptional repression of OPRM1 may be relieved by interaction of MECP2 with SMARCA4 (BRG1), a component of the chromatin remodeling SWI/SNF complex (Hwang et al. 2009). MECP2-mediated repression of OPRM1 involves the SIN3A co-repressor complex (Hwang et al. 2010). In the mouse model of MECP2 duplication syndrome, OPRM1 transcription in the amygdala and hippocampus is increased compared to wild-type mice (Samaco et al. 2012).
R-HSA-9017954 (Reactome) Based on studies in mice, MECP2 binds to the promoter of the OPRM1 gene, encoding Mu-type opioid receptor (Hwang et al. 2008, Hwang et al. 2010, Vucetic et al. 2011, Samaco et al. 2012). MECP2 binds to the OPRM1 promoter together with the SIN3A co-repressor complex, and MECP2 binding correlates with hypermethylation of the promoter region of OPRM1 (Hwang et al. 2009, Hwang et al. 2010).
R-HSA-9017983 (Reactome) Based on studies in mice, MECP2 binds to the promoter of the CRH gene, encoding corticotropin-releasing hormone (corticoliberin) (McGill et al. 2006, Samaco et al. 2012). MECP2 preferentially binds to the CRH promoter with a repressive dimethylation of histone H3 (McGill et al. 2006).
R-HSA-9017988 (Reactome) Based on studies in mice, MECP2 represses transcription from the CRH gene promoter (McGill et al. 2006). Mice with the loss of function of Mecp2 exhibit overexpression of Crh (McGill et al. 2006). Surprisingly, mice with Mecp2 gene duplication, which serve as a model for the MECP2 duplication syndrome, also overexpress Crh (Samaco et al. 2012).
R-HSA-9018594 (Reactome) MECP2 and lamin B receptor (LBR) associate at the inner side of the nuclear envelope. The interaction involves the linker region of MECP2 and appears to happen in heterochromatin regions at the nuclear periphery (Guarda et al. 2009).
R-HSA-9020504 (Reactome) Based on study in rats, MECP2 binds to methylated GRIN2B (NR2B) gene promoter, encoding glutamate (NMDA) receptor subunit epsilon-2. Methylation of the GRIN2B promoter and the subsequent MECP2 binding is promoted by increased neuronal activity and suppressed by low neuronal activity (Lee et al. 2008).
R-HSA-9020513 (Reactome) Based on the study in rats, transcription of the GRIN2B (NR2B) gene, encoding glutamate (NMDA) receptor subunit epsilon-2, is inhibited by promoter methylation and subsequent MECP2 binding. GRIN2B promoter methylation and MECP2 binding are stimulated by neuronal activity. Suppression of neuronal activity leads to demethylation of the GRIN2B promoter and increased GRIN2B transcription (Lee et al. 2008).
R-HSA-9021182 (Reactome) MicroRNA miR-132 is complementary to the 3'UTR of long MECP2 transcripts (>10 kb), which are predominantly expressed in the brain. Based on studies in mice and rats, miR-132 reduces both mRNA and protein levels of MECP2 and was confirmed to be specific for MECP2 mRNA by the 3'UTR-luciferase reporter gene assay (Klein et al. 2007, Su et al. 2015).

miR-132 levels increase in response to BDNF signaling in a CREB-dependent way (Vo et al. 2005, Klein et al. 2007, Lyu et al. 2016). In patients with major depressive disorder, miR-132 levels are increased while MECP2 and BDNF levels are decreased (Su et al. 2015).

R-HSA-9021183 (Reactome) Based on studies in mice and rats, miR-132 reduces both mRNA and protein levels of MECP2. miR-132 is therefore expected to function in the context of the endonucleolytic RISC, and possibly also non-endonucleolytic RISC. MicroRNA miR-132 is complementary to the 3'UTR of long MECP2 transcripts (>10 kb), which are predominantly expressed in the brain (Klein et al. 2007, Su et al. 2015). Based on sequence similarity, human MECP2 mRNA is also predicted to be a miR-132 target.
R-HSA-9021847 (Reactome) Based on studies in mice, transcription of the CREB1 gene is directly stimulated by binding of MECP2 to the CREB1 promoter region (Chahrour et al. 2008).
R-HSA-9021851 (Reactome) Based on studies in mice, MECP2 binds the promoter region of the CREB1 gene (Chahrour et al. 2008).
R-HSA-9021888 (Reactome) Based on studies in mice, MECP2 forms a complex with CREB1 (Chahrour et al. 2008, Chen et al. 2013).
R-HSA-9021919 (Reactome) Based on studies in mice, the complex of MECP2 and CREB1 binds the promoter region of the STT gene, encoding somatostatin (Chahrour et al. 2008).
R-HSA-9021935 (Reactome) Based on studies in mice, transcription of the SST gene, encoding somatostatin, is synergistically stimulated by MECP2 and CREB1, which form a complex at the SST promoter (Chahrour et al. 2008).
R-HSA-9021944 (Reactome) Based on studies in mice, MECP2 binds the promoter region of the RBFOX1 (A2BP1) gene, encoding RNA binding protein fox-1 homolog 1, also known as Ataxin-2-binding protein 1 or Fox-1 homolog A (Chahrour et al. 2008).
R-HSA-9021945 (Reactome) Based on studies in mice, MECP2 binds the promoter region of the GAMT gene, encoding guanidinoacetate N-methyltransferase, which plays an important role during nervous system development (Chahrour et al. 2008).
R-HSA-9021946 (Reactome) Based on studies in mice, MECP2 binds the promoter region of the GPRIN1 gene, encoding G protein-regulated inducer of neurite outgrowth 1 (Chahrour et al. 2008).
R-HSA-9021948 (Reactome) Based on studies in mice, MECP2 directly stimulates transcription of the GPRIN1 gene, encoding G protein-regulated inducer of neurite outgrowth 1 (Chahrour et al. 2008).
R-HSA-9021949 (Reactome) Based on studies in mice, transcription of the MEF2C gene is directly inhibited by MECP2 (Chahrour et al. 2008). MEF2C encodes myocyte-specific enhancer factor 2C, a transcription factor involved in hippocampus-dependent learning and memory (Barbosa et al. 2008).
R-HSA-9021950 (Reactome) Based on studies in mice, MECP2 binds the promoter region of the MEF2C gene, encoding myocyte-specific enhancer factor 2C (Chahrour et al. 2008).
R-HSA-9021951 (Reactome) Based on studies in mice, MECP2 stimulates transcription of the OPRK1 gene, encoding G-coupled kappa-type opioid receptor (Chahrour et al. 2008).
R-HSA-9021952 (Reactome) Based on studies in mice, transcription of the RBFOX1 (A2BP1) gene, encoding RNA binding protein fox-1 homolog 1 (also known as Ataxin-2-binding protein 1 or Fox-1 homolog A) is directly inhibited by MECP2 (Chahrour et al. 2008).
R-HSA-9021953 (Reactome) Based on studies in mice, transcription of the GAMT gene, encoding guanidinoacetate N-methyltransferase, is directly stimulated by MECP2 (Chahrour et al. 2008).
R-HSA-9021954 (Reactome) Based on studies in mice, MECP2 binds the promoter region of the OPRK1 gene, encoding G-protein coupled kappa-type opioid receptor (Chahrour et al. 2008).
R-HSA-9022175 (Reactome) Based on studies in mice, the complex of MECP2 and CREB1 binds to a hypermethylated CpG island in the 5' flanking region of the SLC2A3 (GLUT3) gene, encoding solute carrier family 2, facilitated glucose transporter member 3 (Chen et al. 2013).
R-HSA-9022186 (Reactome) Based on studies in mice, transcription of the SLC2A3 (GLUT3) gene, encoding solute carrier family 2, facilitated glucose transporter member 3, is directly stimulated by the complex of MECP2 and CREB1. In the mouse brain, expression of the Slc2a3 gene is developmentally regulated, peaking at postnatal day 14, which correlates with hypermethylation of the 5' flanking region CpG island (Chen et al. 2013).
R-HSA-9022314 (Reactome) Nuclear serine/threonine protein kinase HIPK2 phosphorylates MECP2 on serine residue S80 (Bracaglia et al. 2009). Phosphorylation of MECP2 at S80 correlates with low neuronal activity. Upon neuronal activation, calcium influx stimulates dephosphorylation at S80 (Tao et al. 2009).
R-HSA-9022315 (Reactome) Based on studies in mice, MECP2, phosphorylated at serine residue S80, binds to DGCR8. The interaction involves the C-terminus of MECP2 and the RNA binding domain-containing C-terminus of DGCR8. Binding to MECP2 may interfere with the interaction between DGCR8 and DROSHA, as well as DGCR8 and primary microRNAs. As DGCR8 and DROSHA form the microprocessor complex which cleaves primary microRNAs (pri-miRNAs) into pre-miRNAs, binding of MECP2 to DGCR8 results in decreased pri-miRNA processing. One of the miRNAs affected by the interaction between MECP2 and DGCR8 is miR-134. miR-134 is highly expressed in brain where it inhibits translation of CREB1, LIMK1 and Pumilio2 mRNAs (Cheng et al. 2014). In addition to DGCR8, MECP2 was reported to bind to other components of the DROSHA microprocessor complex, including DROSHA. Instead of preventing formation of the microprocessor complex, MECP2 was reported to modulate its activity, targeting the complex to specific microRNAs. One of the microRNAs whose processing into a mature product is enhanced in the presence of MECP2 is miR-199a. Expression of several proteins that inhibit mTOR signaling is negatively regulated by miR-199a, creating a mechanistic link between MECP2 loss-of-function and decreased mTOR signaling in Rett syndrome (Tsujimura et al. 2015).
R-HSA-9022359 (Reactome) Based on studies in rat neurons, neuronal activity induces binding of the MECP2, in complex with SIN3A and HDAC1, to the promoter of the GRIA2 (GLUR2) gene, encoding glutamate receptor 2. Prior phosphorylation of MECP2 on serine residue S423 (corresponding to mouse and rat S421), triggered by neuronal activity, may be required (Qiu et al. 2012).
R-HSA-9022365 (Reactome) Based on studies in rat, transcription of the GRIA2 (GLUR2) gene, encoding glutamate receptor 2, is inhibited by binding of the MECP2:SIN3A:HDAC1 complex to the GRIA2 gene promoter. MECP2-mediated regulation of GRIA2 expression is involved in synaptic scaling (Qiu et al. 2012).
R-HSA-9022453 (Reactome) MECP2 binds to DNA containing 5-hydroxymethylcytosine (5hmC-DNA), a DNA modification associated with transcriptional activation (Mellen et al. 2012).
R-HSA-9022456 (Reactome) MECP2 binds to DNA containing 5-methylcytosine (5mC-DNA), a DNA modification associated with transcriptional repression (Mellen et al. 2012). MECP2 binds to 5-methyl cytosine both in the context of CpG islands and outside of CpG islands (Chen et al. 2015).
R-HSA-9022625 (Reactome) Based on studies in mice, both isoforms of MECP2, MECP2_e1 and MECP2_e2, bind to transcription factor FOXG1, with MECP2_e2 binding more strongly. Increased expression of Mecp2_e2 may contribute to neuronal death and this function of Mecp2_e2 may be inhibited by FoxG1 (Dastidar et al. 2012). FOXG1 mutations can, in addition to MECP2 and CDKL5 mutations, also cause Rett syndrome (Ariani et al. 2008).
R-HSA-9022728 (Reactome) Based on studies in mice, MECP2 directly inhibits transcription of the FKBP5 gene, encoding peptidyl-prolyl cis-trans isomerase involved in trafficking of glucocorticoid receptors. Fkbp5 level is increased in Mecp2 null mice (Nuber et al. 2005, Urdinguio et al. 2008).
R-HSA-9022734 (Reactome) Based on studies in mice, MECP2 binds the methylated promoter region of the FKBP5 gene, encoding peptidyl-prolyl cis-trans isomerase involved in trafficking of glucocorticoid receptors (Nuber et al. 2005, Urdinguio et al. 2008).
R-HSA-9022764 (Reactome) Based on studies in mice, MECP2 directly inhibits transcription of the SGK1 gene encoding serum/glucocorticoid-regulated kinase 1. Sgk1 level is increased in Mecp2 null mice (Nuber et al. 2005).
R-HSA-9022770 (Reactome) Based on studies in mice, MECP2 binds the promoter of the SGK1 gene, encoding serum/glucocorticoid-regulated kinase 1 (Nuber et al. 2005).
R-HSA-9022870 (Reactome) Based on studies in mice, MECP2 directly inhibits transcription of the MOBP gene, encoding myelin-associated oligodendrocyte basic protein. Mopb levels are increased in Mecp2 null mice (Urdinguio et al. 2008). MECP2-mediated inhibition of MOBP transcription was also reported in rats (Sharma et al. 2015).
R-HSA-9022872 (Reactome) Based on studies in mice, MECP2 binds to the promoter of the MOBP gene, encoding myelin-associated oligodendrocyte basic protein (Urdinguio et al. 2008).
R-HSA-9022934 (Reactome) Based on studies in mice, MECP2 directly stimulates transcription of the GAD1 (GAD67) gene, encoding glutamate decarboxylase, an enzyme involved in GABA synthesis (Chao et al. 2010).
R-HSA-9022935 (Reactome) Based on studies in mice, MECP2 directly binds the promoter region of the GAD1 (GAD67) gene, encoding glutamate decarboxylase 1, an enzyme involved in GABA synthesis (Chao et al. 2010).
R-HSA-9022941 (Reactome) Based on studies in mice, MECP2 directly binds the promoter region of the GAD2 (GAD65) gene, encoding glutamate decarboxylase 2, an enzyme involved in GABA synthesis (Chao et al. 2010).
R-HSA-9022942 (Reactome) Based on studies in mice, MECP2 stimulates transcription of the GAD2 (GAD65) gene, encoding glutamate decarboxylase 2, an enzyme involved in GABA synthesis (Chao et al. 2010, He et al. 2014).
R-HSA-9023132 (Reactome) Based on studies in mice, AURKB phosphorylates MECP2 at serine residue S423 in dividing adult neuronal progenitor cells (Li et al. 2014).
R-HSA-9023345 (Reactome) Based on studies in mice, increased MECP2 occupancy of the NOTCH1 gene promoter, correlates with decreased transcription of NOTCH1. MECP2 therefore inhibits NOTCH1 transcription. Increased occupancy of the NOTCH1 promoter by MECP2 also results in decreased expression of NOTCH targets HES3 and HES5 (Li et al. 2014).
R-HSA-9023346 (Reactome) Based on studies in mice, MECP2 binds the promoter of the NOTCH1 gene. Binding of MECP2 to the NOTCH1 gene promoter is inhibited by AURKB-mediated phosphorylation of MECP2 at serine residue S423 (Li et al. 2014).
R-HSA-9023348 (Reactome) Based on studies in mice, MECP2 binds the promoter of DLL1 gene, encoding NOTCH ligand Delta 1. Binding of MECP2 to the DLL1 gene promoter is inhibited by AURKB-mediated phosphorylation of MECP2 at serine residue S423 (Li et al. 2014).
R-HSA-9023351 (Reactome) Based on studies in mice, increased MECP2 occupancy of the DLL1 gene promoter, encoding NOTCH ligand Delta 1, correlates with decreased transcription of DLL1. MECP2 therefore inhibits DLL1 transcription (Li et al. 2014).
R-HSA-9023538 (Reactome) Based on studies in mice, MECP2 binds the promoter region of the PTPN1 (PTP1B) gene, encoding Tyrosine-protein phosphatase non-receptor type 1 (Krishnan et al. 2015).
R-HSA-9023549 (Reactome) MECP2 directly represses PTPN1 (PTP1B) gene transcription in both human and mouse cells (Krishnan et al. 2015). PTPN1 can dephosphorylated BDNF receptor TRKB, which negatively regulates BDNF signaling. Increased PTPN1 level, which is a consequence of the loss of function of MECP2, interferes with BDNF signaling (Krishnan et al. 2015).
R-HSA-9023592 (Reactome) Based on studies in mice, MECP2 binds to HTT (Huntingtin), predominantly in the nucleus. Mutant HTT, containing expanded polyglutamine tract (polyQ), as seen in Huntington's disease, binds to MECP2 more strongly than the wild type protein. Mutant HTT was reported to increase MECP2-mediated repression of BDNF transcription, which could underlie BDNF downregulation observed in Huntington's disease (McFarland et al. 2013).
R-HSA-9615490 (Reactome) Based on studies in rat cells, activated CREB1 binds to evolutionarily conserved cAMP response elements (CREs) in the promoter region of the MIR132 gene, encoding microRNA miR-132 (Vo et al. 2005).
R-HSA-9615501 (Reactome) Based on studies in rat and mouse cells, CREB1 induces transcription of the MIR132 gene, encoding miR-132 microRNA (Vo et al. 2005, Lyu et al. 2016). Activation of CREB1 by phosphorylation at serine residue S133 in response to PTEN knockdown results in increased levels of miR-132 (Lyu et al. 2016).
R-HSA-9615536 (Reactome) Based on studies in mouse neurons, MECP2 and SOX2 simultaneously bind to the promoter region of the MIR137 gene, encoding microRNA miR-137 (Szulwach et al. 2010).
R-HSA-9615554 (Reactome) Based on studies in mouse neurons, MECP2 and SOX2 directly repress transcription from the MIR137 gene, encoding microRNA miR-137 (Szulwach et al. 2010, Lyu et al. 2016).
R-HSA-9615570 (Reactome) Based on sequence complementarity and 3'UTR luciferase reporter assays in both human and mouse model systems, microRNA miR-137 binds the 3'UTR of PTEN mRNA (Lyu et al. 2016, Thomas et al. 2017). It is uncertain whether miR-137 functions within the nonendonucleolytic or the endonucleolytic RISC or both.
R-HSA-9615571 (Reactome) Based on studies in both human and mouse model systems, translation of PTEN mRNA is inhibited by microRNA miR-137 (Lyu et al. 2016, Thomas et al. 2017).
R-HSA-9615801 (Reactome) Based on studies in mice, MECP2 binds to the promoter region of IRAK1 gene, encoding a serine/threonine protein kinase involved in activation of NFKB-mediated transcription. MECP2-mediated regulation of IRAK1 transcription may be specific to cortical neurons (Kishi et al. 2016).
R-HSA-9615829 (Reactome) Based on studies in mice, MECP2 represses IRAK1 gene transcription. MECP2-mediated regulation of IRAK1 gene expression may be limited to cortical neurons. IRAK1 is a serine/threonine protein kinase that activates NFKB-mediated transcription. Irak1 is upregulated in the cortex of Mecp2 null mice and some of the Rett syndorome features, such as reduced dendritic complexity and decreased life span, can be ameliorated by attenuation of Nfkb signaling (Kishi et al. 2016). MECP2 may also regulate IRAK1 levels indirectly, by up-regulating microRNA miR-146a, which targets IRAK1 mRNA (Urdinguio et al. 2010).
RBFOX1 geneR-HSA-9021944 (Reactome)
RBFOX1 geneR-HSA-9021952 (Reactome)
RBFOX1ArrowR-HSA-9021952 (Reactome)
SGK1 geneR-HSA-9022764 (Reactome)
SGK1 geneR-HSA-9022770 (Reactome)
SGK1ArrowR-HSA-9022764 (Reactome)
SIN3A:HDAC1,HDAC2 dimersR-HSA-9005995 (Reactome)
SLC2A3 geneR-HSA-9022175 (Reactome)
SLC2A3 geneR-HSA-9022186 (Reactome)
SLC2A3ArrowR-HSA-9022186 (Reactome)
SOX2R-HSA-9615536 (Reactome)
SST geneR-HSA-9021919 (Reactome)
SST geneR-HSA-9021935 (Reactome)
SomatostatinArrowR-HSA-9021935 (Reactome)
TRPC3 geneR-HSA-9005988 (Reactome)
TRPC3 geneR-HSA-9005994 (Reactome)
TRPC3(1-848)ArrowR-HSA-9005994 (Reactome)
miR-132 RISCArrowR-HSA-9615501 (Reactome)
miR-132 RISCR-HSA-9021182 (Reactome)
miR-137 RISCArrowR-HSA-9615554 (Reactome)
miR-137 RISCR-HSA-9615570 (Reactome)
p-S133-CREB1 homodimerR-HSA-9021888 (Reactome)
p-S133-CREB1 homodimerR-HSA-9615490 (Reactome)
p-S133-CREB1:MIR132 geneArrowR-HSA-9615490 (Reactome)
p-S133-CREB1:MIR132 geneArrowR-HSA-9615501 (Reactome)
p-S423-MECP2ArrowR-HSA-9006992 (Reactome)
p-S423-MECP2ArrowR-HSA-9023132 (Reactome)
p-S80-MECP2ArrowR-HSA-9022314 (Reactome)
p-S80-MECP2R-HSA-9022315 (Reactome)
p-T308-MECP2ArrowR-HSA-8986937 (Reactome)

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