E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex
Open accessAbstract
Despite biochemical and genetic data suggesting that E2F and pRB (pocket protein) families regulate transcription via chromatin-modifying factors, the precise mechanisms underlying gene regulation by these protein families have not yet been defined in a physiological setting. In this study, we have investigated promoter occupancy in wild-type and pocket protein-deficient primary cells. We show that corepressor complexes consisting of histone deacetylase (HDAC1) and mSin3B were specifically recruited to endogenous E2F-regulated promoters in quiescent cells. These complexes dissociated from promoters once cells reached late G 1, coincident with gene activation. Interestingly, recruitment of HDAC1 complexes to promoters depended absolutely on p107 and p130, and required an intact E2F-binding site. In contrast, mSin3B recruitment to certain promoters did not require p107 or p130, suggesting that recruitment of this corepressor can occur via E2F-dependent and -independent mechanisms. Remarkably, loss of pRB had no effect on HDAC1 or mSin3B recruitment. p107/p130 deficiency triggered a dramatic loss of E2F4 nuclear localization as well as transcriptional derepression, which is suggested by nucleosome mapping studies to be the result of localized hyperacetylation of nucleosomes proximal to E2F-binding sites. Taken together, these findings show that p130 escorts E2F4 into the nucleus and, together with corepressor complexes that contain mSin3B and/or HDAC1, directly represses transcription from target genes as cells withdraw from the cell cycle.
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In G1 and quiescent cells, Rb is not detected on E2F target promoters, whereas p107 and p130 are readily detected.
“recent reports have been unable to detect Rb on E2F target promoters in G1 and quiescent cells (Rayman et al., 2002; Takahashi et al., 2000). In contrast, p107 and p130 were readily detected. While we confirm these reports”
From Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence (2003) · cites this paper as Rayman et al., 2002
In “Recruitment of E2F and pRB family members in mouse cells” (page unavailable), the paper reports no detectable pRB binding to the promoters studied and detects p130 and p107 in quiescent mouse cells. It also explicitly says p107 was not associated with promoters in quiescent human cells, so the unqualified claim that both p107 and p130 were readily detected in quiescent cells is too broad. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPrevious attempts to detect RB bound to specific E2F target promoters in growing or quiescent cells failed or gave contrasting results.
“Previous attempts to detect RB bound to specific E2F target promoters in growing or quiescent cells have failed or yielded contrasting results (Cam et al., 2004; Rayman et al., 2002; Wells et al., 2000)”
From Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence (2010) · cites this paper as Rayman et al., 2002
In human cells, RB is dispensable for cell cycle exit into quiescence; any RB family member can repress E2F target genes in this setting.
“In human cells, we see that RB is dispensable for cell cycle exit into quiescence – instead, any RB family member could repress E2F target genes in this setting [see also (Rayman et al., 2002)];”
From Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence (2010) · cites this paper as Rayman et al., 2002
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References 48 · Cited by 288
Research works printed but not linked: 3
- Ferreira, R., Magnaghi-Jaulin, L., Robin, P., Harel-Bellan, A., and Trouche, D. 1998. The three members of the pocket proteins family share the ability to repress E2F activity through re- cruitment of a histone deacetylase. Proc. Natl. Acad. Sci. 95: 10493-10498.
- Harrington, E.A., Bruce, J.L., Harlow, E., and Dyson, N. 1998. pRB plays an essential role in cell cycle arrest induced by DNA damage. Proc. Natl. Acad. Sci. 95: 11945-11950.
- Lindeman, G.J., Gaubatz, S., Livingston, D.M., and Ginsberg, D. 1997. The subcellular localization of E2F-4 is cell-cycle de- pendent. Proc. Natl. Acad. Sci. 94: 5095-5100.
- Authors
- Rayman, J. B., Takahashi, Y., Indjeian, V. B., Dannenberg, J.-H., Catchpole, S., Watson, R. J., te Riele, H., & Dynlacht, B. D.
- Affiliations
- Harvard University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2002-04-15
- Volume
- 16
- Issue
- 8
- Pages
- 933-947
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC152357
- OpenAlex
- W2171756101
- Cited by
- 288
- References
- 48
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 9 · 2020: 6 · 2019: 4 · 2018: 7 · 2017: 8 · 2016: 6 · 2015: 8 · 2014: 11 · 2013: 9 · 2012: 16
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA77245-02, R01CA077245)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- E2F transcription factors, transcriptional repression, HDAC1, corepressor complex, p107, p130, retinoblastoma protein, cell cycle, G1 phase, nucleosome acetylation, E2F binding sites, promoter binding, chromatin modification
- MeSH terms
- Acetylation, Animals, Binding Sites, Cell Cycle, Cells, Cultured, DNA-Binding Proteins, Fibroblasts, Histone Deacetylases, Nuclear Proteins, Nucleosomes, Phosphoproteins, Promoter Regions, Genetic, Protein Binding, Proteins, Repressor Proteins, Transcription Factors, Retinoblastoma Protein, 3T3 Cells, Cell Cycle Proteins, Gene Silencing, Macromolecular Substances, E2F Transcription Factors, E2F4 Transcription Factor, Retinoblastoma-Like Protein p130, Retinoblastoma-Like Protein p107, Mice, Histone Deacetylase 1
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