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Intact Nucleosomal Context Enables Chromodomain Reader MRG15 to Distinguish H3K36me3 from - Me2

73 Pages Posted: 20 Jul 2020 Sneak Peek Status: Under Review

See all articles by Sarah Faulkner

Sarah Faulkner

University of Oxford - Department of Chemistry

Anthony M. Couturier

University of Oxford - Sir William Dunn School of Pathology

Brian Josephson

University of Oxford - Department of Chemistry

Tom Watts

University of Oxford - Department of Chemistry

Benjamin G. Davis

University of Oxford - Chemistry Research Laboratory

Fumiko Esashi

University of Oxford - Sir William Dunn School of Pathology

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Abstract

A wealth of in vivo evidence demonstrates the physiological importance of histone H3 trimethylation at lysine 36 (H3K36me3), to which chromodomain-containing proteins, such as MRG15, bind preferentially compared to their dimethyl (H3K36me2) counterparts. However, in vitro studies using isolated H3 peptides have failed to recapitulate a causal interaction. Here, we show that MRG15 can clearly discriminate between synthetic, fully intact model nucleosomes containing H3K36me2 and H3K36me3. MRG15 docking studies, along with experimental observations and nucleosome structure analysis suggest a model where the H3K36 side chain is sequestered in intact nucleosomes via a hydrogen bonding interaction with the DNA backbone, which is abrogated when the third methyl group is added to form H3K36me3. Hence, this mechanism provides a ‘methyl-switch’ for context-dependent reader selectivity. These results highlight the importance of such intra-chromatin interactions in understanding epigenetic regulation, a feature which is absent in commonly-used peptide or histone-only models.

Suggested Citation

Faulkner, Sarah and Couturier, Anthony M. and Josephson, Brian and Watts, Tom and Davis, Benjamin G. and Esashi, Fumiko, Intact Nucleosomal Context Enables Chromodomain Reader MRG15 to Distinguish H3K36me3 from - Me2. Available at SSRN: https://ssrn.com/abstract=3639614 or http://dx.doi.org/10.2139/ssrn.3639614
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Sarah Faulkner

University of Oxford - Department of Chemistry ( email )

Oxford, OX1 3QR
United Kingdom

Anthony M. Couturier

University of Oxford - Sir William Dunn School of Pathology ( email )

South Parks Road
Oxford, OX1 3RE
United Kingdom

Brian Josephson

University of Oxford - Department of Chemistry ( email )

Oxford, OX1 3QR
United Kingdom

Tom Watts

University of Oxford - Department of Chemistry ( email )

Oxford, OX1 3QR
United Kingdom

Benjamin G. Davis

University of Oxford - Chemistry Research Laboratory ( email )

12 Mansfield Road
Oxford, OX1 3TA
United Kingdom

Fumiko Esashi (Contact Author)

University of Oxford - Sir William Dunn School of Pathology ( email )

South Parks Road
Oxford, OX1 3RE
United Kingdom

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