Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains
Open accessPublished version of a preprint
Abstract
Promoters of developmental genes in embryonic stem cells (ESCs) are marked by histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 in an asymmetric nucleosomal conformation, with each sister histone H3 carrying only one of the two marks. These bivalent domains are thought to poise genes for timely activation upon differentiation. Here, we show that asymmetric bivalent nucleosomes recruit repressive H3K27me3 binders but fail to enrich activating H3K4me3 binders, thereby promoting a poised state. Strikingly, the bivalent mark combination further promotes recruitment of specific chromatin proteins that are not recruited by each mark individually, including the lysine acetyltransferase (KAT) complex KAT6B. Knockout of KAT6B blocks neuronal differentiation, demonstrating that KAT6B is critical for proper bivalent gene expression during ESC differentiation. These findings reveal how readout of the bivalent histone marks directly promotes a poised state at developmental genes while highlighting how nucleosomal asymmetry is critical for histone mark readout and function.
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Cites
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 · see citing works
Chromatin repressive complexes in stem cells, development, and cancer
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- Authors
- Bryan, E., Valsakumar, D., Idigo, N. J., Warburton, M., Webb, K. M., McLaughlin, K. A., Spanos, C., Lenci, S., Major, V., Ambrosi, C., Andrews, S., Baubec, T., Rappsilber, J., & Voigt, P.
- Affiliations
- Wellcome Centre for Cell Biology (GB)
- Babraham Institute (GB)
- University of Zurich (CH)
- Utrecht University (NL)
- Corresponding author
- Voigt, Philipp
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2025-02
- Volume
- 85
- Issue
- 3
- Pages
- 471-489.e12
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W4405834795
- Cited by
- 16
- References
- 3
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 2 · 2023: 1
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Biotechnology and Biological Sciences Research Council
- European Research Council
- Wellcome Trust
- Swiss National Science Foundation
- 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 › Chromatin Remodeling and Cancer
- Keywords
- bivalent domains, H3K4me3, H3K27me3, embryonic stem cells, KAT6B, histone acetyltransferase, neuronal differentiation, developmental gene expression
- MeSH terms
- Mouse Embryonic Stem Cells, Animals, Cell Differentiation, Histones, Methylation, Neurons, Nucleosomes, Promoter Regions, Genetic, Protein Binding, Gene Expression Regulation, Developmental, Histone Code, Mice, Histone Acetyltransferases, Embryonic Stem Cells, Neurogenesis
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