Binding of regulatory proteins to nucleosomes is modulated by dynamic histone tails

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dc.contributor.authorPeng, Yunhuien
dc.contributor.authorLi, Shuxiangen
dc.contributor.authorOnufriev, Alexey V.en
dc.contributor.authorLandsman, Daviden
dc.contributor.authorPanchenko, Anna R.en
dc.date.accessioned2022-03-30T12:07:08Zen
dc.date.available2022-03-30T12:07:08Zen
dc.date.issued2021-09-06en
dc.description.abstractLittle is known about the roles of histone tails in modulating nucleosomal DNA accessibility and its recognition by other macromolecules. Here we generate extensive atomic level conformational ensembles of histone tails in the context of the full nucleosome, totaling 65 microseconds of molecular dynamics simulations. We observe rapid conformational transitions between tail bound and unbound states, and characterize kinetic and thermodynamic properties of histone tail-DNA interactions. Different histone types exhibit distinct binding modes to specific DNA regions. Using a comprehensive set of experimental nucleosome complexes, we find that the majority of them target mutually exclusive regions with histone tails on nucleosomal/linker DNA around the super-helical locations +/- 1, +/- 2, and +/- 7, and histone tails H3 and H4 contribute most to this process. These findings are explained within competitive binding and tail displacement models. Finally, we demonstrate the crosstalk between different histone tail post-translational modifications and mutations; those which change charge, suppress tail-DNA interactions and enhance histone tail dynamics and DNA accessibility. The intrinsic disorder of histone tails poses challenges in their characterization. Here the authors apply extensive molecular dynamics simulations of the full nucleosome to show reversible binding to DNA with specific binding modes of different types of histone tails, where charge-altering modifications suppress tail-DNA interactions and may boost interactions between nucleosomes and nucleosome-binding proteins.en
dc.description.notesY.P. and D.L. were supported by the Intramural Research Program of the National Library of Medicine at the U.S. National Institutes of Health. A.R.P. was, in part, supported by the Intramural Research Program of the National Library of Medicine at the U.S. National Institutes of Health. S.L. and A.R.P. were supported by the Department of Pathology and Molecular Medicine, Queen's University, Canada. A.O. was supported by the funding from NIH R21GM134404. A.R.P. is the recipient of a Senior Canada Research Chair in Computational Biology and Biophysics and a Senior Investigator Award from the Ontario Institute of Cancer Research, Canada. This study utilized the high-performance computational resources from the Biowulf cluster at the National Institutes of Health (https://hpc.nih.gov/systems/) and Compute Canada (https://docs.computecanada.ca).en
dc.description.sponsorshipIntramural Research Program of the National Library of Medicine at the U.S. National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Library of Medicine (NLM); Department of Pathology and Molecular Medicine, Queen's University, Canada; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R21GM134404]; Senior Canada Research Chair in Computational Biology and Biophysics; Ontario Institute of Cancer Research, Canadaen
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41467-021-25568-6en
dc.identifier.eissn2041-1723en
dc.identifier.issue1en
dc.identifier.other5280en
dc.identifier.pmid34489435en
dc.identifier.urihttp://hdl.handle.net/10919/109500en
dc.identifier.volume12en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleBinding of regulatory proteins to nucleosomes is modulated by dynamic histone tailsen
dc.title.serialNature Communicationsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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