Title | Oncohistone mutations enhance chromatin remodeling and alter cell fates. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Bagert, JD, Mitchener, MM, Patriotis, AL, Dul, BE, Wojcik, F, Nacev, BA, Feng, L, C Allis, D, Muir, TW |
Journal | Nat Chem Biol |
Volume | 17 |
Issue | 4 |
Pagination | 403-411 |
Date Published | 2021 04 |
ISSN | 1552-4469 |
Keywords | Animals, 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> |
DOI | 10.1038/s41589-021-00738-1 |
Alternate Journal | Nat Chem Biol |
PubMed ID | 33649601 |
PubMed Central ID | PMC8174649 |
Grant List | P30 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 |