Article ; Online: Oncohistone mutations enhance chromatin remodeling and alter cell fates.
2021 Volume 17, Issue 4, Page(s) 403–411
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- ... ...
| 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. |
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| MeSH term(s) | Animals ; Cell Differentiation/genetics ; Chromatin/genetics ; Chromatin Assembly and Disassembly/genetics ; Chromatin Assembly and Disassembly/physiology ; Gene Library ; Histones/genetics ; Humans ; Mutation/genetics ; Neoplasms/genetics ; Nucleosomes/genetics ; Protein Binding ; Protein Domains ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcriptional Activation |
| Chemical Substances | Chromatin ; Histones ; Nucleosomes ; Transcription Factors |
| Language | English |
| Publishing date | 2021-03-01 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2202962-X |
| ISSN | 1552-4469 ; 1552-4450 |
| ISSN (online) | 1552-4469 |
| ISSN | 1552-4450 |
| DOI | 10.1038/s41589-021-00738-1 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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