Oncohistone mutations enhance chromatin remodeling and alter cell fates.

TitleOncohistone mutations enhance chromatin remodeling and alter cell fates.
Publication TypeJournal Article
Year of Publication2021
AuthorsBagert, JD, Mitchener, MM, Patriotis, AL, Dul, BE, Wojcik, F, Nacev, BA, Feng, L, C Allis, D, Muir, TW
JournalNat Chem Biol
Volume17
Issue4
Pagination403-411
Date Published2021 04
ISSN1552-4469
KeywordsAnimals, Cell Differentiation, Chromatin, Chromatin Assembly and Disassembly, Gene Library, Histones, Humans, Mutation, Neoplasms, Nucleosomes, Protein Binding, Protein Domains, Transcription Factors, Transcriptional Activation
Abstract

<p>Whole-genome sequencing data mining efforts have revealed numerous histone mutations in a wide range of cancer types. These occur in all four core histones in both the tail and globular domains and remain largely uncharacterized. Here we used two high-throughput approaches, a DNA-barcoded mononucleosome library and a humanized yeast library, to profile the biochemical and cellular effects of these mutations. We identified cancer-associated mutations in the histone globular domains that enhance fundamental chromatin remodeling processes, histone exchange and nucleosome sliding, and are lethal in yeast. In mammalian cells, these mutations upregulate cancer-associated gene pathways and inhibit cellular differentiation by altering expression of lineage-specific transcription factors. This work represents a comprehensive functional analysis of the histone mutational landscape in human cancers and leads to a model in which histone mutations that perturb nucleosome remodeling may contribute to disease development and/or progression.</p>

DOI10.1038/s41589-021-00738-1
Alternate JournalNat Chem Biol
PubMed ID33649601
PubMed Central IDPMC8174649
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R37 GM086868 / GM / NIGMS NIH HHS / United States
F32 GM123659 / GM / NIGMS NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
R01 GM086868 / GM / NIGMS NIH HHS / United States
K08 CA245212 / CA / NCI NIH HHS / United States
F32 GM131632 / GM / NIGMS NIH HHS / United States