Mutations on the surface of HDAC1 reveal molecular determinants of specific complex assembly and their requirement for gene regulation
Open accessPublished version of a preprint
Abstract
Histone deacetylase 1 and 2 (HDAC1/2) regulate histone acetylation as catalytic and structural components of six unique multiprotein complex families: SIN3, NuRD, CoREST, MIDAC, MIER, and RERE. Co-immunoprecipitation of HDAC1-Flag followed by mass spectrometry revealed that 92% of HDAC1 in mouse embryonic stem cells resides in three complexes, NuRD (49%), CoREST (28%), and SIN3 (15%). We compared the structures of MTA1:HDAC1 and MIDEAS:HDAC1 to identify critical binding residues on the surface of HDAC1. Surprisingly, a single mutation, Y48E, disrupts binding to all complexes except SIN3. Rescue experiments performed with HDAC1–Y48E in HDAC1/2 double-knockout cells showed that retention of SIN3 binding alone is sufficient for cell viability. Gene expression and histone acetylation patterns were perturbed in both Y48E and a second mutant cell line, HDAC1–E63R, indicating that cells require a full repertoire of the HDAC1/2 complexes to regulate their transcriptome appropriately. Comparative analysis of MTA1/HDAC1 and SIN3B/HDAC2 structures confirmed the differential modes of HDAC1 recruitment, with Y48 interacting with ELM2/SANT domain-containing proteins, but not SIN3. The E63R mutation shows markedly reduced binding to NuRD and MiDAC complexes but retains some CoREST binding. We provide novel molecular insights into the abundance, co-factors and assemblies of this crucial family of chromatin modifying machines.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Accurate structure prediction of biomolecular interactions with AlphaFold 3
Abramson, J., Adler, J., Dunger, J., Evans, R., Green, T., Pritzel, A., Ronneberger, O., Willmore, L., Ballard, A. J., Bambrick, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07487-w · Cited by 15,861 · see citing works
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · cited 1× · see citing works
“To estimate the abundance of individual proteins, we calculated intensity-based absolute quantification (iBAQ, [ 31 ]) values and manually curated proteins into SIN3A / B, NuRD, CoR-EST, MiDAC, MIER, and RERE complexes (Fig.”
TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity
Williams, K., Christensen, J., Pedersen, M. T., Johansen, J. V., Cloos, P. A. C., Rappsilber, J., & Helin, K. (2011) · Nature · doi:10.1038/nature10066 · Cited by 1,021 · see citing works
Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes
Bantscheff, M., Hopf, C., Savitski, M. M., Dittmann, A., Grandi, P., Michon, A.-M., Schlegl, J., Abraham, Y., Becher, I., Bergamini, G., et al. (2011) · Nature Biotechnology · doi:10.1038/nbt.1759 · Cited by 659 · see citing works
Histone Deacetylases and SAP18, a Novel Polypeptide, Are Components of a Human Sin3 Complex
Zhang, Y., Iratni, R., Erdjument-Bromage, H., Tempst, P., & Reinberg, D. (1997) · Cell · doi:10.1016/s0092-8674(00)80216-0 · Cited by 578 · see citing works
An Oct4-Centered Protein Interaction Network in Embryonic Stem Cells
van den Berg, D. L. C., Snoek, T., Mullin, N. P., Yates, A., Bezstarosti, K., Demmers, J., Chambers, I., & Poot, R. A. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.02.014 · Cited by 542 · see citing works
Kelly, R. D. W., & Cowley, S. M. (2013) · Biochemical Society Transactions · doi:10.1042/bst20130010 · Cited by 297 · see citing works
Self-citationThe functional interactome landscape of the human histone deacetylase family
Joshi, P., Greco, T. M., Guise, A. J., Luo, Y., Yu, F., Nesvizhskii, A. I., & Cristea, I. M. (2013) · Molecular Systems Biology · doi:10.1038/msb.2013.26 · Cited by 289 · see citing works
Insights into the activation mechanism of class I HDAC complexes by inositol phosphates
Watson, P. J., Millard, C. J., Riley, A. M., Robertson, N. S., Wright, L. C., Godage, H. Y., Cowley, S. M., Jamieson, A. G., Potter, B. V. L., & Schwabe, J. W. R. (2016) · Nature Communications · doi:10.1038/ncomms11262 · Cited by 244 · see citing works
Self-citationTargeting Class I Histone Deacetylases in a “Complex” Environment
Millard, C. J., Watson, P. J., Fairall, L., & Schwabe, J. W. R. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.12.006 · Cited by 180 · see citing works
Self-citationMechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex
Wan, M. S. M., Muhammad, R., Koliopoulos, M. G., Roumeliotis, T. I., Choudhary, J. S., & Alfieri, C. (2023) · Nature Communications · doi:10.1038/s41467-023-38276-0 · Cited by 32 · see citing works
Flagged first, then by citations
- Authors
- Alshehri, A., Baker, I.-M., English, D. M., Fairall, L., Collins, M. O., Schwabe, J. W. R., & Cowley, S. M.
- Affiliations
- University of Leicester (GB)
- University of Sheffield (GB)
- Corresponding author
- Schwabe, John W R
- Cowley, Shaun M
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2025-09-05
- Volume
- 53
- Issue
- 17
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC12448893
- OpenAlex
- W4414346486
- Cited by
- 5
- References
- 11
- Citations by year
- 2026: 4 · 2025: 1
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council
- Wellcome Trust (222493/Z/21/Z, MR/W00190X/1)
- BBSRC (BB/P021689/1)
- MRC (MR/X012220/1, MR/W00190X/1)
- UKRI
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- 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
- Keywords
- HDAC1, histone deacetylase, protein complex formation, NuRD complex, CoREST complex, MTA1, SANT domain, histone acetylation, chromatin regulation, gene expression, mouse embryonic stem cells, protein-protein interaction
- MeSH terms
- Mouse Embryonic Stem Cells, Acetylation, Animals, Gene Expression Regulation, Histone Deacetylases, Histones, Humans, Models, Molecular, Mutation, Protein Binding, Repressor Proteins, Trans-Activators, Mice, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sin3 Histone Deacetylase and Corepressor Complex, Histone Deacetylase 1, Histone Deacetylase 2, Co-Repressor Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
