@article{4086,
  keywords = {Animals, Humans, Transcription Factors, Protein Binding, Mutation, Gene Library, Transcriptional Activation, Cell Differentiation, Histones, Nucleosomes, Chromatin, Neoplasms, Chromatin Assembly and Disassembly, Protein Domains},
  author = {John Bagert and Michelle Mitchener and Agata Patriotis and Barbara Dul and Felix Wojcik and Benjamin Nacev and Lijuan Feng and C David Allis and Tom Muir},
  title = {Oncohistone mutations enhance chromatin remodeling and alter cell fates.},
  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> },
  year = {2021},
  journal = {Nat Chem Biol},
  volume = {17},
  pages = {403-411},
  month = {2021 Apr},
  issn = {1552-4469},
  doi = {10.1038/s41589-021-00738-1},
  language = {eng},
}