Oncohistone mutations enhance chromatin remodeling and alter cell fates

John D. Bagert, Michelle M. Mitchener, Agata L. Patriotis, Barbara E. Dul, Felix Wojcik, Benjamin A. Nacev, Lijuan Feng, C. David Allis, Tom W. Muir

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)403-411
Number of pages9
JournalNature Chemical Biology
Volume17
Issue number4
DOIs
StatePublished - Apr 2021

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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