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.
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McStay B, Grummt I.; ''The epigenetics of rRNA genes: from molecular to chromosome biology.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Majumder S, Ghoshal K, Datta J, Smith DS, Bai S, Jacob ST.; ''Role of DNA methyltransferases in regulation of human ribosomal RNA gene transcription.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Grummt I, Längst G.; ''Epigenetic control of RNA polymerase I transcription in mammalian cells.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Evers R, Grummt I.; ''Molecular coevolution of mammalian ribosomal gene terminator sequences and the transcription termination factor TTF-I.''; PubMedEurope PMCScholia
Grummt I.; ''Different epigenetic layers engage in complex crosstalk to define the epigenetic state of mammalian rRNA genes.''; PubMedEurope PMCScholia
Birch JL, Zomerdijk JC.; ''Structure and function of ribosomal RNA gene chromatin.''; PubMedEurope PMCScholia
Preuss S, Pikaard CS.; ''rRNA gene silencing and nucleolar dominance: insights into a chromosome-scale epigenetic on/off switch.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.
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.
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).
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.
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.
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).
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.
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.
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.
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promoter escape
complexAnnotated Interactions
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.
promoter escape
complex