Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains

Elana Bryan; Devisree Valsakumar; Nwamaka J. Idigo; Marie Warburton; Kimberly M. Webb; Katy A. McLaughlin; Christos Spanos; Simone Lenci; Viktoria Major; Christina Ambrosi; Simon Andrews; Tuncay Baubec; Juri Rappsilber; Philipp Voigt

doi:10.1016/j.molcel.2024.12.002

Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains

Elana Bryan, Devisree Valsakumar, Nwamaka J. Idigo, Marie Warburton, Kimberly M. Webb, Katy A. McLaughlin, Christos Spanos, Simone Lenci, Viktoria Major, Christina Ambrosi, Simon Andrews, Tuncay Baubec, Juri Rappsilber, Philipp Voigt

Research output: Contribution to journal › Article › peer-review

Abstract

Summary 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.

Original language	English
Pages (from-to)	471-489.e12
Number of pages	32
Journal	Molecular Cell
Volume	85
Issue number	3
Early online date	27 Dec 2024
DOIs	https://doi.org/10.1016/j.molcel.2024.12.002
Publication status	Published - 6 Feb 2025

Keywords / Materials (for Non-textual outputs)

chromatin
transcription
histone methylation
histone acetylation
bivalent domains
embryonic stem cells
differentiation
Polycomb

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10.1016/j.molcel.2024.12.002

1-s2.0-S1097276524009973-mainFinal published version, 9.27 MBLicence: Creative Commons: Attribution (CC-BY)

https://www.sciencedirect.com/science/article/pii/S1097276524009973

Cite this

@article{424b40c9ff014131bfa2c83e696e1754,

title = "Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains",

abstract = "Summary 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.",

keywords = "chromatin, transcription, histone methylation, histone acetylation, bivalent domains, embryonic stem cells, differentiation, Polycomb",

author = "Elana Bryan and Devisree Valsakumar and Idigo, {Nwamaka J.} and Marie Warburton and Webb, {Kimberly M.} and McLaughlin, {Katy A.} and Christos Spanos and Simone Lenci and Viktoria Major and Christina Ambrosi and Simon Andrews and Tuncay Baubec and Juri Rappsilber and Philipp Voigt",

note = "We are grateful to Till Bartke for helpful discussions and advice on nucleosome pull-down assays. We thank Tania Auchynnikava for help with initial MS analysis and Giulia Bartolomucci for technical support in generating knockout and knockin ESC lines. We thank Logan McKay and Faye Cruickshank for performing FTICR mass spectrometry analysis of recombinant histones. We are grateful to D{\'o}nal O{\textquoteright}Carroll and Peter Rugg-Gunn for critical reading of the manuscript. We thank Adrian Bird, Atlanta Cook, and Ken Sawin for fruitful discussions and insightful comments on this work. We also thank all members of our labs for helpful discussions. ",

year = "2025",

month = feb,

day = "6",

doi = "10.1016/j.molcel.2024.12.002",

language = "English",

volume = "85",

pages = "471--489.e12",

journal = "Molecular Cell",

issn = "1097-2765",

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TY - JOUR

T1 - Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains

AU - Bryan, Elana

AU - Valsakumar, Devisree

AU - Idigo, Nwamaka J.

AU - Warburton, Marie

AU - Webb, Kimberly M.

AU - McLaughlin, Katy A.

AU - Spanos, Christos

AU - Lenci, Simone

AU - Major, Viktoria

AU - Ambrosi, Christina

AU - Andrews, Simon

AU - Baubec, Tuncay

AU - Rappsilber, Juri

AU - Voigt, Philipp

N1 - We are grateful to Till Bartke for helpful discussions and advice on nucleosome pull-down assays. We thank Tania Auchynnikava for help with initial MS analysis and Giulia Bartolomucci for technical support in generating knockout and knockin ESC lines. We thank Logan McKay and Faye Cruickshank for performing FTICR mass spectrometry analysis of recombinant histones. We are grateful to Dónal O’Carroll and Peter Rugg-Gunn for critical reading of the manuscript. We thank Adrian Bird, Atlanta Cook, and Ken Sawin for fruitful discussions and insightful comments on this work. We also thank all members of our labs for helpful discussions.

PY - 2025/2/6

Y1 - 2025/2/6

N2 - Summary 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.

AB - Summary 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.

KW - chromatin

KW - transcription

KW - histone methylation

KW - histone acetylation

KW - bivalent domains

KW - embryonic stem cells

KW - differentiation

KW - Polycomb

UR - https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE229987

UR - https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE250570

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UR - https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD015988

UR - https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041753

UR - https://doi.org/10.17632/5h3565w2p7.1

U2 - 10.1016/j.molcel.2024.12.002

DO - 10.1016/j.molcel.2024.12.002

M3 - Article

SN - 1097-2765

VL - 85

SP - 471-489.e12

JO - Molecular Cell

JF - Molecular Cell

IS - 3

ER -

Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

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The Hidden Cell Discovery Research Platform

Core funding for the Wellcome Centre for Cell Biology

Proteomics at the Wellcome Trust Centre for Cell Biology (WTCCB) and School of Biological Sciences (SBS), Edinburgh

Cite this

Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Other files and links

Fingerprint

Projects

The Hidden Cell Discovery Research Platform

Core funding for the Wellcome Centre for Cell Biology

Proteomics at the Wellcome Trust Centre for Cell Biology (WTCCB) and School of Biological Sciences (SBS), Edinburgh

Cite this