NoRC negatively regulates rRNA expression (Homo sapiens)

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2, 4-7, 121, 389, 11910cytosolnucleoplasmMe2K10-HIST1H3A MNAT1 TTF1 SMARCA5 MBD2 Me2K10-HIST1H3A TTF-I:Sal BoxPOLR1B POLR2K BAZ2A Me2K-10-H3F3A ARID4B POLR1C RNA Polymerase Ipromoter escapecomplexSUDS3 Sal BoxHIST1H4 Sal Box HDAC2 DNMT3B POLR2F Me2K-10-HIST2H3A SIN3 HDACcorepressor complexTAF1C Me2K-10-HIST2H3A AdoMetERCC3 ARID4B POLR1E POLR2L DNMT1Me2K-10-HIST2H3A Ac-TAF1B TAF1D Me2K-10-H3F3A POLR1D pRNA (intergenicrRNA) TTF1H3F3A ERCC2 HDAC2HIST2H3A SMARCA5 POLR1A CDK7 Chromatin withH3K9me2, 5mCGTF2H1 Chromatin (H4K5ac,H4K8ac, H4K16ac)SAP30 Chromatin (H3K9me2,5mC):MBD2HIST1H4 CD3EAP AdoHcyIntergenic rRNAtranscriptGTF2H2 HDAC1NTPTWISTNB DNMT1 SAP30BP SAP130 Me2K-10-H3F3A CCNH TBP GTF2H4 GTF2H5 UBTF BAZ2A AdoMetPOLR2E SAP30BP MBD2NoRCTAF1A SAP18 SAP130 HIST1H3A SAP30L CH3COO-HDAC1 Chromatin (H3K9me2)NoRC:pRNA:HDAC:DNMTMe2K10-HIST1H3A DNMT3BGTF2H3 pRNA (intergenicrRNA)POLR2H HIST1H4 SAP18 AdoHcySUDS3 Sal Box ZNRD1 4xAcK-HIST1H4A SAP30 SAP30L 1


Description

Only about half of the rRNA gene copies in a cell are expressed. The remaining copies are silenced by modifications to histones and DNA (reviewed in Santoro and Grummt 2001, Grummt 2007, Preuss and Pikaard 2007, Birch and Zomerdijk 2008, McStay and Grummt 2008, Grummt and Langst 2013). The promoters of silenced rRNA gene copies have methylated cytosine and histone H3 dimethylated at lysine-9. As inferred from mouse, silencing is initiated by recruitment of the Nucleolar Remodeling Complex (NoRC) to the promoter through interaction with TTF-I and intergenic spacer transcripts. NoRC shifts a nucleosome near the start of rRNA transcription into a more repressive location and recruits Histone Deacetylase 1 and 2 (HDAC1, HDAC2) and DNA Methyltransferase 1 and 3b (DNMT1, DNMT3b). Interaction with a Histone Methyltransferase is also assumed. Deacetylation of histones is required for DNA methylation but not for methylation of histone H3. Methylcytosine at the rRNA promoter binds Methyl Domain Binding protein 2 (MBD2) which inhibits expression of the rRNA gene. Source:Reactome.

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Bibliography

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  1. McStay B, Grummt I.; ''The epigenetics of rRNA genes: from molecular to chromosome biology.''; PubMed Europe PMC Scholia
  2. Shiao YH, Lupascu ST, Gu YD, Kasprzak W, Hwang CJ, Fields JR, Leighty RM, Quiñones O, Shapiro BA, Alvord WG, Anderson LM.; ''An intergenic non-coding rRNA correlated with expression of the rRNA and frequency of an rRNA single nucleotide polymorphism in lung cancer cells.''; PubMed Europe PMC Scholia
  3. Majumder S, Ghoshal K, Datta J, Smith DS, Bai S, Jacob ST.; ''Role of DNA methyltransferases in regulation of human ribosomal RNA gene transcription.''; PubMed Europe PMC Scholia
  4. Espada J, Ballestar E, Santoro R, Fraga MF, Villar-Garea A, Németh A, Lopez-Serra L, Ropero S, Aranda A, Orozco H, Moreno V, Juarranz A, Stockert JC, Längst G, Grummt I, Bickmore W, Esteller M.; ''Epigenetic disruption of ribosomal RNA genes and nucleolar architecture in DNA methyltransferase 1 (Dnmt1) deficient cells.''; PubMed Europe PMC Scholia
  5. Grummt I, Längst G.; ''Epigenetic control of RNA polymerase I transcription in mammalian cells.''; PubMed Europe PMC Scholia
  6. Anosova I, Melnik S, Tripsianes K, Kateb F, Grummt I, Sattler M.; ''A novel RNA binding surface of the TAM domain of TIP5/BAZ2A mediates epigenetic regulation of rRNA genes.''; PubMed Europe PMC Scholia
  7. Ghoshal K, Majumder S, Datta J, Motiwala T, Bai S, Sharma SM, Frankel W, Jacob ST.; ''Role of human ribosomal RNA (rRNA) promoter methylation and of methyl-CpG-binding protein MBD2 in the suppression of rRNA gene expression.''; PubMed Europe PMC Scholia
  8. Evers R, Grummt I.; ''Molecular coevolution of mammalian ribosomal gene terminator sequences and the transcription termination factor TTF-I.''; PubMed Europe PMC Scholia
  9. Grummt I.; ''Different epigenetic layers engage in complex crosstalk to define the epigenetic state of mammalian rRNA genes.''; PubMed Europe PMC Scholia
  10. Birch JL, Zomerdijk JC.; ''Structure and function of ribosomal RNA gene chromatin.''; PubMed Europe PMC Scholia
  11. Preuss S, Pikaard CS.; ''rRNA gene silencing and nucleolar dominance: insights into a chromosome-scale epigenetic on/off switch.''; PubMed Europe PMC Scholia
  12. Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A.; ''MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex.''; PubMed Europe PMC Scholia
  13. Santoro R, Grummt I.; ''Molecular mechanisms mediating methylation-dependent silencing of ribosomal gene transcription.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
123264view09:03, 9 July 2022EgonwReplaced an old Ensembl identifier
114939view16:46, 25 January 2021ReactomeTeamReactome version 75
113384view11:45, 2 November 2020ReactomeTeamReactome version 74
112588view15:56, 9 October 2020ReactomeTeamReactome version 73
103040view12:32, 2 February 2019EgonwReplace a deprecated Ensembl identifier with a ChEBI one (for RNA) also used by Reactome.
101504view11:37, 1 November 2018ReactomeTeamreactome version 66
101040view21:18, 31 October 2018ReactomeTeamreactome version 65
100571view19:51, 31 October 2018ReactomeTeamreactome version 64
100120view16:36, 31 October 2018ReactomeTeamreactome version 63
99670view15:06, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93778view13:35, 16 August 2017ReactomeTeamreactome version 61
93307view11:20, 9 August 2017ReactomeTeamreactome version 61
88072view08:56, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86390view09:17, 11 July 2016ReactomeTeamreactome version 56
83237view10:27, 18 November 2015ReactomeTeamVersion54
81344view12:52, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
4xAcK-HIST1H4A ProteinP62805 (Uniprot-TrEMBL)
ARID4B ProteinQ4LE39 (Uniprot-TrEMBL)
Ac-TAF1B ProteinQ53T94 (Uniprot-TrEMBL)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
BAZ2A ProteinQ9UIF9 (Uniprot-TrEMBL)
CCNH ProteinP51946 (Uniprot-TrEMBL)
CD3EAP ProteinO15446 (Uniprot-TrEMBL)
CDK7 ProteinP50613 (Uniprot-TrEMBL)
CH3COO-MetaboliteCHEBI:15366 (ChEBI)
Chromatin (H3K9me2)ComplexR-HSA-3211683 (Reactome)
Chromatin (H3K9me2, 5mC):MBD2ComplexR-HSA-427343 (Reactome)
Chromatin (H4K5ac, H4K8ac, H4K16ac)ComplexR-HSA-5226874 (Reactome)
Chromatin with H3K9me2, 5mCComplexR-HSA-5226877 (Reactome)
DNMT1 ProteinP26358 (Uniprot-TrEMBL)
DNMT1ProteinP26358 (Uniprot-TrEMBL)
DNMT3B ProteinQ9UBC3 (Uniprot-TrEMBL)
DNMT3BProteinQ9UBC3 (Uniprot-TrEMBL)
ERCC2 ProteinP18074 (Uniprot-TrEMBL)
ERCC3 ProteinP19447 (Uniprot-TrEMBL)
GTF2H1 ProteinP32780 (Uniprot-TrEMBL)
GTF2H2 ProteinQ13888 (Uniprot-TrEMBL)
GTF2H3 ProteinQ13889 (Uniprot-TrEMBL)
GTF2H4 ProteinQ92759 (Uniprot-TrEMBL)
GTF2H5 ProteinQ6ZYL4 (Uniprot-TrEMBL)
H3F3A ProteinP84243 (Uniprot-TrEMBL)
HDAC1 ProteinQ13547 (Uniprot-TrEMBL)
HDAC1ProteinQ13547 (Uniprot-TrEMBL)
HDAC2 ProteinQ92769 (Uniprot-TrEMBL)
HDAC2ProteinQ92769 (Uniprot-TrEMBL)
HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
Intergenic rRNA transcriptProteinENSG00000266658 (ENSEMBL)
MBD2 ProteinQ9UBB5 (Uniprot-TrEMBL)
MBD2ProteinQ9UBB5 (Uniprot-TrEMBL)
MNAT1 ProteinP51948 (Uniprot-TrEMBL)
Me2K-10-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Me2K-10-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
Me2K10-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
NTPR-ALL-30595 (Reactome)
NoRC:pRNA:HDAC:DNMTComplexR-HSA-427410 (Reactome)
NoRCComplexR-HSA-427339 (Reactome)
POLR1A ProteinO95602 (Uniprot-TrEMBL)
POLR1B ProteinQ9H9Y6 (Uniprot-TrEMBL)
POLR1C ProteinO15160 (Uniprot-TrEMBL)
POLR1D ProteinQ9Y2S0 (Uniprot-TrEMBL)
POLR1E ProteinQ9GZS1 (Uniprot-TrEMBL)
POLR2E ProteinP19388 (Uniprot-TrEMBL)
POLR2F ProteinP61218 (Uniprot-TrEMBL)
POLR2H ProteinP52434 (Uniprot-TrEMBL)
POLR2K ProteinP53803 (Uniprot-TrEMBL)
POLR2L ProteinP62875 (Uniprot-TrEMBL)
RNA Polymerase I

promoter escape

complex		ComplexR-HSA-73717 (Reactome)
SAP130 ProteinQ9H0E3 (Uniprot-TrEMBL)
SAP18 ProteinO00422 (Uniprot-TrEMBL)
SAP30 ProteinO75446 (Uniprot-TrEMBL)
SAP30BP ProteinQ9UHR5 (Uniprot-TrEMBL)
SAP30L ProteinQ9HAJ7 (Uniprot-TrEMBL)
SIN3 HDAC corepressor complexComplexR-HSA-352501 (Reactome)
SMARCA5 ProteinO60264 (Uniprot-TrEMBL)
SUDS3 ProteinQ9H7L9 (Uniprot-TrEMBL)
Sal Box ProteinENSG00000266658 (ENSEMBL) Named the "Sal Box" as a Sal I restriction endonuclease site is located within the sequence. An 18 base pair sequence element found in multiple copies in the nontranscribed spacer downstream of the 18S rRNA coding region. This element provides the termination signal for ribosomal gene transcription.
Sal BoxENSG00000266658 (ENSEMBL) Named the "Sal Box" as a Sal I restriction endonuclease site is located within the sequence. An 18 base pair sequence element found in multiple copies in the nontranscribed spacer downstream of the 18S rRNA coding region. This element provides the termination signal for ribosomal gene transcription.
TAF1A ProteinQ15573 (Uniprot-TrEMBL)
TAF1C ProteinQ15572 (Uniprot-TrEMBL)
TAF1D ProteinQ9H5J8 (Uniprot-TrEMBL)
TBP ProteinP20226 (Uniprot-TrEMBL)
TTF-I:Sal BoxComplexR-HSA-74977 (Reactome)
TTF1 ProteinQ15361 (Uniprot-TrEMBL)
TTF1ProteinQ15361 (Uniprot-TrEMBL)
TWISTNB ProteinQ3B726 (Uniprot-TrEMBL)
UBTF ProteinP17480 (Uniprot-TrEMBL)
ZNRD1 ProteinQ9P1U0 (Uniprot-TrEMBL)
pRNA (intergenic rRNA) ProteinENSG00000266658 (ENSEMBL)
pRNA (intergenic rRNA)ProteinENSG00000266658 (ENSEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AdoHcyArrowR-HSA-433672 (Reactome)
AdoHcyArrowR-HSA-5227490 (Reactome)
AdoMetR-HSA-433672 (Reactome)
AdoMetR-HSA-5227490 (Reactome)
CH3COO-ArrowR-HSA-433672 (Reactome)
Chromatin (H3K9me2)ArrowR-HSA-433672 (Reactome)
Chromatin (H3K9me2)R-HSA-5227490 (Reactome)
Chromatin (H3K9me2, 5mC):MBD2ArrowR-HSA-427337 (Reactome)
Chromatin (H4K5ac, H4K8ac, H4K16ac)R-HSA-433672 (Reactome)
Chromatin with H3K9me2, 5mCArrowR-HSA-5227490 (Reactome)
Chromatin with H3K9me2, 5mCR-HSA-427337 (Reactome)
DNMT1R-HSA-427409 (Reactome)
DNMT3BR-HSA-427409 (Reactome)
HDAC1R-HSA-427409 (Reactome)
HDAC2R-HSA-427409 (Reactome)
Intergenic rRNA transcriptArrowR-HSA-427366 (Reactome)
Intergenic rRNA transcriptR-HSA-427394 (Reactome)
MBD2R-HSA-427337 (Reactome)
NTPR-HSA-427366 (Reactome)
NoRC:pRNA:HDAC:DNMTArrowR-HSA-427409 (Reactome)
NoRC:pRNA:HDAC:DNMTmim-catalysisR-HSA-433672 (Reactome)
NoRC:pRNA:HDAC:DNMTmim-catalysisR-HSA-5227490 (Reactome)
NoRCR-HSA-427409 (Reactome)
R-HSA-427337 (Reactome) Methyl Binding Domain protein 2 (MBD2) binds 5-methylcytosine residues in DNA (Ng et al. 1999) and may recruit further silencing complexes. MBD2 has been shown to specifically bind 5-methylcytosine in the promoters of rRNA gene copies to reduce promoter activity (Ghoshal et al. 2004).
R-HSA-427366 (Reactome) As inferred from mouse cell models, intergenic spacer regions (IGS) located between rRNA transcription units contain upstream promoters and are transcribed by RNA Polymerase I. The IGS transcripts originate approximately 2 Kb upstream of the start of rRNA transcription and proceed though the main promoter of the rRNA gene.
R-HSA-427394 (Reactome) As inferred from mouse cell models, long Intergenic Spacer RNA of about 2 Kb is cleaved to yield shorter fragments of 150-300 nucleotides. The enzyme responsible for the cleavage is unknown.
R-HSA-427409 (Reactome) As inferred from mouse cell models, the Nucleolar Remodeling Complex (NoRC) comprises TIP5 (BAZ2A) and the chromatin remodeller SNF2H (SMARCA5). The TAM domain of TIP5 (BAZ2A) binds promoter-associated RNA (pRNA) transcribed from the intergenic spacer region of rDNA. Binding is not sequence-specific but depends on the secondary structure of the RNA. The pRNA bound by TIP5 is required to direct the complex to the main promoter of the rRNA gene possibly by triple helix formation between pRNA and the rDNA. The PHD domain of TIP5 binds histone H4 acetylated at lysine-16. Transcription Termination Factor-I (TTF-I) binds to a promoter-proximal terminator (T0 site) in the rDNA and interacts with the TIP5 subunit of NoRC. NoRC also interacts with the SIN3-HDAC complex, HDAC1, HDAC2, DNMT1, and DNMT3B. DNMT3B interacts with a triple helix formed by pRNA and the rDNA. HDAC1, DNMT1, and DNMT3B have been shown to be required for proper DNA methylation of silenced rRNA gene copies, although the catalytic activity of DNMT3B was not required (Majumder et al. 2006).
R-HSA-433672 (Reactome) As inferred from mouse cell models, histones in silenced rRNA gene copies are deacetylated by HDAC1 (and possibly HDAC2), which is part of the SIN3-HDAC complex bound to NoRC. The PHD domain of the TIP5 (BAZ2A) component of NoRC binds acetylated lysine-16 of histone H4. The residues of histone H4 that are deacetylatd are lysine-5, lysine-8, and lysine-12.
In the main promoters of silenced rRNA gene copies, histone H3 is methylated on lysine-9 (H3K9) by an unknown histone methyltransferase. H3K9 methylation is still observed when deacetylation is inhibited, therefore histone methylation does not depend on deacetylation. However histone deacetylation is required for DNA methylation. Significantly more dimethylation than trimethylation is observed.
R-HSA-5227490 (Reactome) From research with human cells (Majumder et al. 2006, Espada et al. 2007) and inferences from mouse cell models, cytosine residues in the main promoter of silenced rRNA gene copiess are methylated by DNMT1 and DNMT3B. DNMT3B directly binds a triple helix formed by pRNA and the main promoter of rDNA. The methylated cytosines prevent binding of the UBF transcription factor, thus preventing transcription of silenced rRNA gene copies. Histone deacetylation is required for DNA methylation.
R-HSA-74987 (Reactome) As inferred from mouse cell models, the Transcription termination factor (TTF1, also known as TTF-1 and TTF-I) binds an 18 base pair sequence element known as the Sal Box found in multiple copies in the nontranscribed spacer downstream of the 28S rRNA coding region. This element is the termination signal for ribosomal gene transcription. Binding of TTF1 mediates the pausing of the elongating transcription complex. TTF1 has a relatively low affinity for purified DNA but binds cooperatively to chromatin. Oligomers of TTF1 interact in trans to bind adjacent intergenic regions and form loops of the rDNA. Binding of TTF1 to the Sal Box is also influenced by interaction of TTF1 with TIP5 and possibly other proteins.
RNA Polymerase I

promoter escape

complex		mim-catalysisR-HSA-427366 (Reactome)
SIN3 HDAC corepressor complexR-HSA-427409 (Reactome)
Sal BoxR-HSA-74987 (Reactome)
TTF-I:Sal BoxArrowR-HSA-74987 (Reactome)
TTF-I:Sal BoxR-HSA-427409 (Reactome)
TTF1ArrowR-HSA-427409 (Reactome)
TTF1R-HSA-74987 (Reactome)
pRNA (intergenic rRNA)ArrowR-HSA-427394 (Reactome)
pRNA (intergenic rRNA)R-HSA-427409 (Reactome)
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