ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (Homo sapiens)

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1-3, 5, 7...6, 11, 13148nucleoplasmH2AFZ HIST2H2AA3 HIST1H2AJ HIST1H2AB HIST1H2BD HIST2H2AC Chromatin (H3K9me2)H2AFJ ChromatinHIST2H2AC DNA Me2K-10-H3F3A CBX3 Me2K10-HIST1H3A AdoHcyHIST1H2AB HIST1H2AJ H2BFS HIST1H2BH HIST1H2AC H2BFS H2AFJ HIST3H2BB DNA H2AFV H2AFZ HIST1H2BB ERCC6 dimerHIST1H2BA ERCC6 HIST1H2BN HIST1H2AC HIST3H2BB H2AFV Me2K-10-HIST2H3A HIST1H2BJ HIST1H2BA EHMT2HIST1H2AD HIST1H2BL H2AFZ HIST2H2BE HIST1H2BN HIST1H2AC HIST1H2BK HIST2H3A MBD3 HIST1H2AD TTF-I:Sal BoxTTF1 HIST1H2BA HIST1H4 HIST1H2AB HIST1H2BM H2AFB1 CHD4 TTF1 H2AFB1 HIST1H2BC HIST3H2BB HIST2H2BE HIST1H2BB DNA HIST1H2BO HDAC1 HIST1H2BD HIST1H2BL HIST1H2BO HIST2H2AA3 MTA1 MTA2 HIST1H2BK HIST1H2BJ HIST1H2BC Chromatin(H3K9me2):CBX3TTF1Me2K-10-HIST2H3A AdoMetMTA3 HIST1H2BM HIST1H2BN HIST1H2BH Me2K10-HIST1H3A CHD3 HIST2H2BE TTF-I:SalBox:CSB:G9a:NuRDHIST1H3A HIST1H2BC Me2K-10-H3F3A HIST2H2AA3 H2AFV HIST1H2BJ HIST1H2BD H2AFJ HIST1H2BB GATAD2B CBX3HIST2H2AC RBBP4 RBBP7 GATAD2A HIST1H4 H2BFS H2AFX HIST1H2BO HIST1H2BM HDAC2 HIST1H2BL HIST1H2BH NuRD complexHIST1H2AD HIST1H4 HIST1H2AJ H3F3A HIST1H2BK H2AFB1 H2AFX H2AFX 4, 109


Description

About half of the rRNA genes in the genome are actively expressed, being transcribed by RNA polymerase I (reviewed in Nemeth and Langst 2008, Bartova et al. 2010, Goodfellow and Zomerdijk 2012, Grummt and Langst 2013). As inferred from mouse, those genes that are expressed are activated by ERCC6 (also known as Cockayne Syndrome protein, CSB) which interacts with TTF-I bound to the T0 terminator region (also know as the Sal Box) of rRNA genes (Yuan et al. 2007, reviewed in Birch and Zomerdijk 2008, Grummt and Langst 2013). ERCC6 recruits the histone methyltransferase EHMT2 (also known as G9a) which dimethylates histone H3 at lysine-9 in the coding region of rRNA genes. The dimethylated lysine is bound by CBX3 (also known as Heterochromatic Protein-1gamma, HP1gamma) and increases expression of the rRNA gene. Continuing dimethylation depends on continuing transcription. Mutations in CSB result in dysregulation of RNA polymerase I transcription, which plays a role in the symptoms of Cockayne Syndrome (reviewed in Hannan et al. 2013). View original pathway at:Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 427389
Reactome-version 
Reactome version: 64
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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  1. Evers R, Grummt I.; ''Molecular coevolution of mammalian ribosomal gene terminator sequences and the transcription termination factor TTF-I.''; PubMed Europe PMC Scholia
  2. Smallwood A, Hon GC, Jin F, Henry RE, Espinosa JM, Ren B.; ''CBX3 regulates efficient RNA processing genome-wide.''; PubMed Europe PMC Scholia
  3. Yuan X, Feng W, Imhof A, Grummt I, Zhou Y.; ''Activation of RNA polymerase I transcription by cockayne syndrome group B protein and histone methyltransferase G9a.''; PubMed Europe PMC Scholia
  4. Bártová E, Horáková AH, Uhlírová R, Raska I, Galiová G, Orlova D, Kozubek S.; ''Structure and epigenetics of nucleoli in comparison with non-nucleolar compartments.''; PubMed Europe PMC Scholia
  5. Shimono K, Shimono Y, Shimokata K, Ishiguro N, Takahashi M.; ''Microspherule protein 1, Mi-2beta, and RET finger protein associate in the nucleolus and up-regulate ribosomal gene transcription.''; PubMed Europe PMC Scholia
  6. 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.''; PubMed Europe PMC Scholia
  7. Németh A, Längst G.; ''Chromatin organization of active ribosomal RNA genes.''; PubMed Europe PMC Scholia
  8. Hannan KM, Sanij E, Rothblum LI, Hannan RD, Pearson RB.; ''Dysregulation of RNA polymerase I transcription during disease.''; PubMed Europe PMC Scholia
  9. Birch JL, Zomerdijk JC.; ''Structure and function of ribosomal RNA gene chromatin.''; PubMed Europe PMC Scholia
  10. 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.''; PubMed Europe PMC Scholia
  11. Lebedev A, Scharffetter-Kochanek K, Iben S.; ''Truncated Cockayne syndrome B protein represses elongation by RNA polymerase I.''; PubMed Europe PMC Scholia
  12. Bradsher J, Auriol J, Proietti de Santis L, Iben S, Vonesch JL, Grummt I, Egly JM.; ''CSB is a component of RNA pol I transcription.''; PubMed Europe PMC Scholia
  13. Christiansen M, Thorslund T, Jochimsen B, Bohr VA, Stevnsner T.; ''The Cockayne syndrome group B protein is a functional dimer.''; PubMed Europe PMC Scholia
  14. Grummt I, Längst G.; ''Epigenetic control of RNA polymerase I transcription in mammalian cells.''; PubMed Europe PMC Scholia
  15. Goodfellow SJ, Zomerdijk JC.; ''Basic mechanisms in RNA polymerase I transcription of the ribosomal RNA genes.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114821view16:32, 25 January 2021ReactomeTeamReactome version 75
113266view11:33, 2 November 2020ReactomeTeamReactome version 74
112481view15:43, 9 October 2020ReactomeTeamReactome version 73
101392view11:28, 1 November 2018ReactomeTeamreactome version 66
100930view21:03, 31 October 2018ReactomeTeamreactome version 65
100468view19:38, 31 October 2018ReactomeTeamreactome version 64
100014view16:21, 31 October 2018ReactomeTeamreactome version 63
99567view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99191view12:43, 31 October 2018ReactomeTeamreactome version 62
93789view13:36, 16 August 2017ReactomeTeamreactome version 61
93323view11:20, 9 August 2017ReactomeTeamreactome version 61
87440view13:40, 22 July 2016MkutmonOntology Term : 'transcription pathway' added !
86410view09:17, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
GeneProduct
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
CBX3 ProteinQ13185 (Uniprot-TrEMBL)
CBX3ProteinQ13185 (Uniprot-TrEMBL)
CHD3 ProteinQ12873 (Uniprot-TrEMBL)
CHD4 ProteinQ14839 (Uniprot-TrEMBL)
Chromatin (H3K9me2):CBX3ComplexR-HSA-427344 (Reactome)
Chromatin (H3K9me2)ComplexR-HSA-3211683 (Reactome)
ChromatinComplexR-HSA-3211736 (Reactome)
DNA R-ALL-29428 (Reactome)
EHMT2ProteinQ96KQ7 (Uniprot-TrEMBL)
ERCC6 ProteinQ03468 (Uniprot-TrEMBL)
ERCC6 dimerComplexR-HSA-5365864 (Reactome)
GATAD2A ProteinQ86YP4 (Uniprot-TrEMBL)
GATAD2B ProteinQ8WXI9 (Uniprot-TrEMBL)
H2AFB1 ProteinP0C5Y9 (Uniprot-TrEMBL)
H2AFJ ProteinQ9BTM1 (Uniprot-TrEMBL)
H2AFV ProteinQ71UI9 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFZ ProteinP0C0S5 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
H3F3A ProteinP84243 (Uniprot-TrEMBL)
HDAC1 ProteinQ13547 (Uniprot-TrEMBL)
HDAC2 ProteinQ92769 (Uniprot-TrEMBL)
HIST1H2AB ProteinP04908 (Uniprot-TrEMBL)
HIST1H2AC ProteinQ93077 (Uniprot-TrEMBL)
HIST1H2AD ProteinP20671 (Uniprot-TrEMBL)
HIST1H2AJ ProteinQ99878 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H2AA3 ProteinQ6FI13 (Uniprot-TrEMBL)
HIST2H2AC ProteinQ16777 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
MBD3 ProteinO95983 (Uniprot-TrEMBL)
MTA1 ProteinQ13330 (Uniprot-TrEMBL)
MTA2 ProteinO94776 (Uniprot-TrEMBL)
MTA3 ProteinQ9BTC8 (Uniprot-TrEMBL)
Me2K-10-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Me2K-10-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
Me2K10-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
NuRD complexComplexR-HSA-4657018 (Reactome)
RBBP4 ProteinQ09028 (Uniprot-TrEMBL)
RBBP7 ProteinQ16576 (Uniprot-TrEMBL)
Sal Box Protein
TTF-I:Sal Box:CSB:G9a:NuRDComplexR-HSA-427352 (Reactome)
TTF-I:Sal BoxComplexR-HSA-74977 (Reactome)
TTF1 ProteinQ15361 (Uniprot-TrEMBL)
TTF1ProteinQ15361 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AdoHcyArrowR-HSA-427336 (Reactome)
AdoMetR-HSA-427336 (Reactome)
CBX3R-HSA-427383 (Reactome)
Chromatin (H3K9me2):CBX3ArrowR-HSA-427383 (Reactome)
Chromatin (H3K9me2)ArrowR-HSA-427336 (Reactome)
Chromatin (H3K9me2)R-HSA-427383 (Reactome)
ChromatinR-HSA-427336 (Reactome)
EHMT2R-HSA-427404 (Reactome)
ERCC6 dimerR-HSA-427404 (Reactome)
NuRD complexR-HSA-427404 (Reactome)
R-HSA-427336 (Reactome) As inferred from mouse, EHMT2 (histone methyltransferase G9a) dimethylates histone H3 at lysine-9 (H3K9me2) in the transcribed region of the rRNA gene. Dimethylation of histone H3 in the transcribed region causes increased rRNA expression, which contrasts with the repressive effect of H3K9me2 in other regions of the genome. The histone binding activity and ATPase activity of CHD4 in the NuRD complex are also needed for activation.
R-HSA-427383 (Reactome) As inferred from mouse, CBX3 (Heterochromatic Protein 1gamma, HP1gamma) binds histone H3 dimethylated at lysine-9 (H3K9me2). In other regions of the genome, CBX3 can be associated with repression of transcription, however dimethylated H3 lysine-9 and CBX3 in the transcribed region of the rRNA gene are associated with enhanced expression. CBX3 bound to gene bodies can facilitate cotranscriptional processing of RNA (Smallwood et al. 2012).
R-HSA-427404 (Reactome) Transcription Termination Factor-I (TTF-I) is a sequence-specific binding protein that binds sites 5' (Tsp and T0 sites) and 3' (T1-10 site) of rRNA genes. As inferred from mouse, when TTF-I is bound to the promoter-proximal T0 site TTF-I either recruits ERCC6 (also known as Cockayne Syndrome Protein, CSB), EHMT2 (also known as histone methyltransferase G9a), and NuRD to activate expression (Shimono et al. 2005, Lebedev et al. 2008) or recruits the Nucleolar Remodeling Complex (NoRC) to repress expression. How one is selected over the other is unknown.
CHD4 and presumably the rest of the NuRD complex is associated with bivalent domains containing H3K4me3 (active chromatin mark) and H3K27me3 (inactive chromatin mark). ERCC6 and EHMT2 appear to cooperate to regulate activation of rRNA expression with ERCC6 mediating the transition to permissive chromatin (Lebedev et al. 2008) and EHMT2 mediating the transition to active chromatin, which involves the positional shift of one nucleosome at the promoter.
R-HSA-74987 (Reactome)
TTF-I:Sal Box:CSB:G9a:NuRDArrowR-HSA-427404 (Reactome)
TTF-I:Sal Box:CSB:G9a:NuRDmim-catalysisR-HSA-427336 (Reactome)
TTF-I:Sal BoxArrowR-HSA-74987 (Reactome)
TTF-I:Sal BoxR-HSA-427404 (Reactome)
TTF1R-HSA-74987 (Reactome)
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