@article{dec964870499416e85a7cca6ef7cde9b,
title = "Oncohistone mutations enhance chromatin remodeling and alter cell fates",
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.].",
author = "Bagert, {John D.} and Mitchener, {Michelle M.} and Patriotis, {Agata L.} and Dul, {Barbara E.} and Felix Wojcik and Nacev, {Benjamin A.} and Lijuan Feng and Allis, {C. David} and Muir, {Tom W.}",
note = "Funding Information: We thank T. Carroll from the Bioinformatics Resource Center at The Rockefeller University and J. Majewski and E. Bareke from McGill University for help and guidance with the RNA-seq analyses. We thank W. Wang and the Princeton Genomics Core Facility for designing the Illumina adaptor sequences and performing NGS on DNA-barcoded MN library experimental samples. We thank A.J. Burton for providing the dead CfaC peptide and H. Liu for providing Cy3-tagged histone H3. Funding support includes grant nos. P01CA196539 (T.W.M. and C.D.A.) and R37-GM086868 (T.W.M.), and we thank members of the Allis and Muir laboratories, especially those members of our collective P01 team. J.D.B. was funded by a postdoctoral fellowship from the US National Institutes of Health (grant no. GM123659). M.M.M. was funded by a postdoctoral fellowship from the US National Institutes of Health (grant no. GM131632). A.L.P. was funded by an Anderson Graduate Fellowship in Cancer Research from the Anderson Cancer Center. F.W. was supported by a postdoctoral fellowship from the German Research Foundation (WO 2039/1-1). B.A.N. was funded by the National Cancer Institute (grant no. 1K08CA245212) and we acknowledge the Memorial Sloan Kettering Cancer Center Support Grant/Core grant (no. P30 CA008748). L.F. was supported by the C. H. Li Memorial Scholar Fund Award. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = apr,
doi = "10.1038/s41589-021-00738-1",
language = "English (US)",
volume = "17",
pages = "403--411",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "4",
}