Nucleosome context regulates chromatin reader preference

Chromatin is more than a simple genome packaging system but rather locally distinguished by histone post-translational modifications (PTMs) that can directly change nucleosome structure and/or be "read" by chromatin-associated proteins to mediate downstream events. An accurate understanding of histone PTM binding preference is vital to explain normal function and pathogenesis and has revealed multiple therapeutic opportunities. Such studies most often use histone peptides, though these cannot represent the full regulatory potential of nucleosome context. Here we apply a range of complementary and easily adoptable biochemical and genomic approaches to interrogate fully defined peptide and nucleosome targets with a diversity of mono- or multivalent chromatin readers. In the resulting data, nucleosome context consistently refined reader binding, and multivalent engagement was more often regulatory than simply additive. This included abrogating binding of the Polycomb group malignant brain tumor (MBT) protein L3MBTL1 to lysine methylated histone tails and confirmation that the CBX7 chromodomain and AT-hook-like motif (CD-ATL) tandem act as a functional unit to confer specificity for H3K27me3. These in vitro nucleosome preferences were confirmed by in vivo reader-CUT&RUN genomic mapping. Such data confirms that more representative chromatin substrates provide greater insight into biological mechanism and human disease.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-10-01
DOI
https://doi.org/10.1093/nar/gkaf1061
Citations
2
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
1.61
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Nucleosome context regulates chromatin reader preference

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Nucleic Acids Research
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Nucleosome context regulates chromatin reader preference

Michael‐Christopher Keogh, Andrea L. Johnstone, Matthew R. Marunde, Susan L. Gloor, Nathan W Hall, Conrad Smith, James R. Bone, Danielle N Maryanski, Luis F. Schachner, Eileen T. McAnarney, Irina K Popova, Ellen N Weinzapfel, Krzysztof Krajewski, Natalia Ledo Husby, Elisa Gibson, Tessa M. Firestone, Martis W. Cowles, Brandon A. Boone, Jaquelyn Sanchez, Kelsey E. Noll, Anup Vaidya, Keli L Rodriguez, R. Watson, Allison R. Hickman, Harrison A. Fuchs, Catherine A. Musselman, Zachary B Gillespie, Katherine Novitzky, Marcus A. Cheek, Sarah A. Howard, Neil L. Kelleher, Alexander S. Lee, Zu‐Wen Sun, Hailey F. Taylor, Emily F Patteson, Peter J. Brown, Matthew J. Meiners, Keith E. Maier, Bryan J. Venters, Ryan J. Ezell, Jamie L McCuiston, Lu Sun, Hannah Willis, Jonathan M. Burg, Laiba F Khan, Victoria T Hsiung
article en
2 citations

Abstract

Chromatin is more than a simple genome packaging system but rather locally distinguished by histone post-translational modifications (PTMs) that can directly change nucleosome structure and/or be "read" by chromatin-associated proteins to mediate downstream events. An accurate understanding of histone PTM binding preference is vital to explain normal function and pathogenesis and has revealed multiple therapeutic opportunities. Such studies most often use histone peptides, though these cannot represent the full regulatory potential of nucleosome context. Here we apply a range of complementary and easily adoptable biochemical and genomic approaches to interrogate fully defined peptide and nucleosome targets with a diversity of mono- or multivalent chromatin readers. In the resulting data, nucleosome context consistently refined reader binding, and multivalent engagement was more often regulatory than simply additive. This included abrogating binding of the Polycomb group malignant brain tumor (MBT) protein L3MBTL1 to lysine methylated histone tails and confirmation that the CBX7 chromodomain and AT-hook-like motif (CD-ATL) tandem act as a functional unit to confer specificity for H3K27me3. These in vitro nucleosome preferences were confirmed by in vivo reader-CUT&RUN genomic mapping. Such data confirms that more representative chromatin substrates provide greater insight into biological mechanism and human disease.

Nucleic Acids ResearchVol. 53(20)
Northwestern University (US), University of North Carolina at Chapel Hill (US), University of Toronto (CA), Structural Genomics Consortium (CA), EpiCypher (United States) (US), University of Colorado Anschutz Medical Campus (US)
Openalex Percentile: Top 14%
Genomics and Chromatin Dynamics
1.61
DOIOpen Access PDFOpenAlex
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