The chromatin remodeling complex NoRC targets HDAC1 to the ribosomal gene promoter and represses RNA polymerase i transcription
Open accessAbstract
Mammalian chromatin remodeling complexes are involved in both activation and repression of transcription. Here, we show that NoRC, a SNF2h- containing nucleolar chromatin remodeling complex, represses ribosomal gene transcription. NoRC-mediated rDNA silencing was alleviated by trichostatin A, indicating that histone deacetylation is causally involved in silencing. Chromatin immunoprecipitation experiments demonstrate that overexpression of TIP5, the large subunit of NoRC, mediates deacetylation of nucleosomes in the vicinity of the rDNA promoter. Protein-protein interaction assays reveal association of TIP5 with the histone deacetylase HDAC1 in vivo and in vitro. Deletion of the C-terminal PHD finger and bromodomain abolishes the interaction of TIP5 and HDAC1, and abrogates transcriptional repression. The results suggest that NoRC silences the rDNA locus by targeting the SIN3 corepressor complex to the rDNA promoter, thereby establishing a repressed chromatin structure.
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Silent rRNA genes in mammalian cells have hypermethylated DNA and regular nucleosomes carrying repressive histone modifications, such as H3K9me3, H4K20me3 and H3K27me3.
“Silent rRNA genes in mammalian cells are known to have hypermethylated DNA and regular nucleosomes carrying repressive histone modifications, such as H3K9me3, H4K20me3 and H3K27me3 (94,95,102,103)”
From Impaired function of rDNA transcription initiation machinery leads to derepression of ribosomal genes with insertions of R2 retrotransposon (2022) · cites this paper as [102]
The Introduction says inactive rDNA copies contain nucleosomes, and the Discussion reports CpG methylation and H3 lysine-9 methylation at silent ribosomal genes. The Discussion does not specify H3K9 trimethylation or report H4K20me3 or H3K27me3; it also says the DNA is methylated without characterizing it as hypermethylated. (LLM, conf=0.88)
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- Santoro,R., Li,J. and Grummt,I. (2002) The nucleolar remodeling complex NoRC silences ribosomal gene transcription. Nat. Genet., in press.
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“I plays a key role in the establishment of both the active and inactive state of rDNA (3–7).”
BackgroundSelf-citationRNA polymerase I in yeast transcribes dynamic nucleosomal rDNA
Jones, H. S., Kawauchi, J., Braglia, P., Amaro, C. A., Kent, N. A., & Proudfoot, N. J. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1199 · Cited by 73 · see citing works
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The Nucleolus: In Genome Maintenance and Repair
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The homeostatic regulation of ribosome biogenesis
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Structure and Epigenetics of Nucleoli in Comparison With Non-nucleolar Compartments
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“This complex can interact with Dnmt1, Dnmt3, and the Sin3 correpressor complex containing histone deacetylases HDAC1 and HDAC2 but not SIRT1 (Santoro et al. 2002; Zhou et al. 2002; McStay and Grummt 2008).”
BackgroundChromatin Turn Ons and Turn Offs of Ribosomal RNA Genes
Lawrence, R. J., & Pikaard, C. S. (2004) · Cell Cycle · doi:10.4161/cc.3.7.983 · Cited by 70 · see citing works
Postepska‐Igielska, A., Krunic, D., Schmitt, N., Greulich‐Bode, K. M., Boukamp, P., & Grummt, I. (2013) · EMBO Reports · doi:10.1038/embor.2013.87 · Cited by 72 · see citing works
“TIP5, the large subunit of NoRC, targets histone-modifying enzymes to rDNA to generate a repressive heterochromatic structure [2,3].”
InfluentialSelf-citationStructure and function of ribosomal RNA gene chromatin
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Epigenetic Programming of the rRNA Promoter by MBD3
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“It has been previously reported through chromatin immunoprecipitation assays, however, that HDAC1 does bind to the rRNA promoter ( 54 ); therefore, a complete lack of these proteins in the nucleolus is unlikely.”
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Chromatin remodeling and human disease
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“…(2015), 7(4), 366–382 doi:10.1093/jmcb/mju038 Published online October 3, 2014 in establishing the heterochromatic state at the rDNA promoter by recruitment of proteins possessing histone-modifying or DNAmethylating activities (Santoro et al., 2002; Zhou et al., 2002; Santoro and Grummt, 2005 ).”
BackgroundInfluentialPosttranslational Modifications of Histones by Methylation
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“HDAC1 is part of several multiprotein complexes (Kelly and Cowley, 2013), including the chromatin remodeling complexes NoRC (nucleolar remodeling complex) and NuRD, which both modulate the epigenetic signature of rRNA genes (Strohner et al., 2001; Zhou et al., 2002; Xie et al., 2012).”
BackgroundSelf-citationCHD8 Associates with Human Staf and Contributes to Efficient U6 RNA Polymerase III Transcription
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“In this process, it is clear that the packaging of DNA into certain chromatin states has a repressive effect on transcription, in particular on the initiation and elongation steps, as histone octamers within nucleosomes can block the binding of transcription initiation factors and hamper the progress of RNA Pol along…”
BackgroundThe silence of the ribosomal RNA genes
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“Histone acetylations, both of H3 and H4, have been connected with active genes [11,12,16,39], and we now link H3 acetylation to chromatin-remodelling events.”
BackgroundThe Role of Long Noncoding RNAs in the Epigenetic Control of Gene Expression
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Gene Regulation by Chromatin Structure: Paradigms Established inDrosophila melanogaster
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Behind the scenes: How RNA orchestrates the epigenetic regulation of gene expression
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“, 2008), the major subunit of the nucleolar remodeling complex (NoRC), an ATP-dependent chromatin remodeling complex that has been shown to repress rRNA transcription through H4 taildependent nucleosome sliding and HDAC1 recruitment (Strohner et al., 2001; Zhou et al., 2002) (Figure 2B).”
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“NoRC associates with repressive factors such as DNA methyltransferases, which methylate rRNA gene promoter sequences (Guetg et al., 2010, 2012; Santoro et al., 2002; Zhou et al., 2002).”
BackgroundSelf-citationNucleolus and rRNA Gene Chromatin in Early Embryo Development
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“NoRC establishes silent rRNA genes through the recruitment of DNA methyltransferases (DNMTs) and histone modifier enzymes, such as histone deacetylase 1 (HDAC1), thereby establishing heterochromatic and repressive structures [20,21,27].”
BackgroundInfluentialSelf-citationFactors Responsible for Modulation of Ribosomal RNA Transcription
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“NoRC is associated with silent rRNA gene copies, and over-expression of TIP5 represses rRNA polymerase I transcription (SANTORO et al. 2002; ZHOU et al. 2002).”
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Histone Fold Protein Dls1p Is Required for Isw2-Dependent Chromatin Remodeling In Vivo
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“chromosomes (11), and a mammalian ISWI complex, No-RC, represses ribosomal DNA transcription (48).”
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“Mammalian complexes have also suggested links between SNF2H activity and HDACs ( Zhou et al, 2002, 2005; Santoro and Grummt, 2005).”
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“NoRC interacts with DNA methyltransferases, histone deacetylases and histone methyltransferases, thereby triggering promoter methylation, heterochromatin formation and transcriptional silencing.(23,27,28) Thus, NoRC coordinates the activities of macromolecular complexes that modify histones, methylate DNA and establis…”
BackgroundSelf-citationATP-Dependent Chromatin Remodeling During Cortical Neurogenesis
Sokpor, G., Castro-Hernández, R., Rosenbusch, J., Staiger, J. F., & Tuoc, T. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00226 · Cited by 60 · see citing works
“…and specifically regulate the expression of ribosomal genes due to the interaction of TIP5 with the transcription termination factor TTF-I and the histone deacetylase HDAC1, resulting in transcriptional repression of target genes (Strohner et al., 2001; Zhou et al., 2002; Manelyte et al., 2014).”
Background
- Authors
- Zhou, Y., Santoro, R., & Grummt, I.
- Affiliations
- German Cancer Research Center (DE)
- Corresponding author
- Grummt, Ingrid
- Venue
- The EMBO Journal
- Published
- 2002-09-02
- Volume
- 21
- Issue
- 17
- Pages
- 4632-4640
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC126197
- OpenAlex
- W2045365624
- Cited by
- 234
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 9 · 2021: 5 · 2020: 8 · 2019: 6 · 2018: 11 · 2017: 6 · 2016: 12 · 2015: 9 · 2014: 10 · 2013: 12 · 2012: 15
- FWCI
- 4.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- norC, HDAC1, histone deacetylation, ribosomal DNA transcription, rDNA silencing, RNA polymerase I, PHD finger, bromodomain, transcriptional repression
- MeSH terms
- Bromodomain Containing Proteins, Acetylation, Animals, Cell Line, Chromatin, Chromosomal Proteins, Non-Histone, DNA, Ribosomal, Histone Deacetylases, Histones, Multienzyme Complexes, Nucleosomes, Promoter Regions, Genetic, Protein Processing, Post-Translational, Recombinant Fusion Proteins, RNA Polymerase I, Transcription, Genetic, Trans-Activators, 3T3 Cells, Protein Structure, Tertiary, Genes, rRNA, Amino Acid Motifs, Gene Silencing, Protein Interaction Mapping, Macromolecular Substances, Mice, Sin3 Histone Deacetylase and Corepressor Complex, Histone Deacetylase 1
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