Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains
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.
Authors
- Kimberly M. Webb (ORCID: https://orcid.org/0000-0002-1908-1272)
- Simon Andrews (ORCID: https://orcid.org/0000-0002-5006-3507)
- Christina M. Ambrosi (ORCID: https://orcid.org/0000-0002-7167-1173)
- Christos Spanos (ORCID: https://orcid.org/0000-0002-4376-8242)
- Tuncay Baubec (ORCID: https://orcid.org/0000-0001-8474-6587)
- Marie Warburton
- Nwamaka J. Idigo (ORCID: https://orcid.org/0000-0002-0723-3793)
- Elana Bryan (ORCID: https://orcid.org/0000-0002-7925-2424)
- Philipp Voigt (ORCID: https://orcid.org/0000-0003-4366-0490)
- Viktoria Major
- Juri Rappsilber (ORCID: https://orcid.org/0000-0001-5999-1310)
- Devisree Valsakumar (ORCID: https://orcid.org/0000-0002-8279-6369)
- Katy McLaughlin (ORCID: https://orcid.org/0000-0001-5128-1883)
- Simone Lenci
Institutions
- Babraham Institute (GB)
- Utrecht University (NL)
- University of Zurich (CH)
- Wellcome Centre for Cell Biology (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Molecular Cell
- Published
- 2024-12-27
- DOI
- https://doi.org/10.1016/j.molcel.2024.12.002
- Citations
- 10
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- Wellcome Trust
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Biotechnology and Biological Sciences Research Council
- H2020 European Research Council