Diverse modes of H3K36me3-guided nucleosomal deacetylation by Rpd3S
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Abstract
Context-dependent dynamic histone modifications constitute a key epigenetic mechanism in gene regulation 1–4 . The Rpd3 small (Rpd3S) complex recognizes histone H3 trimethylation on lysine 36 (H3K36me3) and deacetylates histones H3 and H4 at multiple sites across transcribed regions 5–7 . Here we solved the cryo-electron microscopy structures of Saccharomyces cerevisiae Rpd3S in its free and H3K36me3 nucleosome-bound states. We demonstrated a unique architecture of Rpd3S, in which two copies of Eaf3–Rco1 heterodimers are asymmetrically assembled with Rpd3 and Sin3 to form a catalytic core complex. Multivalent recognition of two H3K36me3 marks, nucleosomal DNA and linker DNAs by Eaf3, Sin3 and Rco1 positions the catalytic centre of Rpd3 next to the histone H4 N-terminal tail for deacetylation. In an alternative catalytic mode, combinatorial readout of unmethylated histone H3 lysine 4 and H3K36me3 by Rco1 and Eaf3 directs histone H3-specific deacetylation except for the registered histone H3 acetylated lysine 9. Collectively, our work illustrates dynamic and diverse modes of multivalent nucleosomal engagement and methylation-guided deacetylation by Rpd3S, highlighting the exquisite complexity of epigenetic regulation with delicately designed multi-subunit enzymatic machineries in transcription and beyond.
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- Authors
- Guan, H., Wang, P., Zhang, P., Ruan, C., Ou, Y., Peng, B., Zheng, X., Lei, J., Li, B., Yan, C., & Li, H.
- Affiliations
- State Key Laboratory of Molecular Oncology (CN)
- Shanghai Jiao Tong University (CN)
- Zhengzhou University (CN)
- Tsinghua University (CN)
- Center for Life Sciences (CN)
- Corresponding author
- Yan, Chuangye
- Li, Haitao
- Venue
- Nature
- Published
- 2023-07-19
- Volume
- 620
- Issue
- 7974
- Pages
- 669-675
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10432269
- OpenAlex
- W4384819932
- Cited by
- 40
- References
- 5
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 11 · 2023: 5
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Natural Science Foundation of China (32030019, 92153302, 91753203, 31725014)
- Tsinghua University
- Fundamental Research Funds for the Central Universities
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- H3K36me3, histone deacetylation, nucleosome, Sin3, Rpd3, H3K4, H3K9, multivalent recognition, histone methylation, Saccharomyces cerevisiae, epigenetic regulation, transcriptional regulation, cryo-EM structure
- MeSH terms
- Acetylation, Acetyltransferases, Chromosomal Proteins, Non-Histone, DNA, Fungal, Histone Deacetylases, Histones, Lysine, Methylation, Nucleosomes, Repressor Proteins, Saccharomyces cerevisiae, Cryoelectron Microscopy, Saccharomyces cerevisiae Proteins, Epigenesis, Genetic, Multiprotein Complexes
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