Lysine 4 of histone H3.3 is required for embryonic stem cell differentiation, histone enrichment at regulatory regions and transcription accuracy

Item Type:	Article
Title:	Lysine 4 of histone H3.3 is required for embryonic stem cell differentiation, histone enrichment at regulatory regions and transcription accuracy
Creators Name:	Gehre, M. and Bunina, D. and Sidoli, S. and Lübke, M.J. and Diaz, N. and Trovato, M. and Garcia, B.A. and Zaugg, J.B. and Noh, K.M.
Abstract:	Mutations in enzymes that modify histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36) have been linked to human disease, yet the role of these residues in mammals is unclear. We mutated K4 or K36 to alanine in the histone variant H3.3 and showed that the K4A mutation in mouse embryonic stem cells (ESCs) impaired differentiation and induced widespread gene expression changes. K4A resulted in substantial H3.3 depletion, especially at ESC promoters; it was accompanied by reduced remodeler binding and increased RNA polymerase II (Pol II) activity. Regulatory regions depleted of H3.3K4A showed histone modification alterations and changes in enhancer activity that correlated with gene expression. In contrast, the K36A mutation did not alter H3.3 deposition and affected gene expression at the later stages of differentiation. Thus, H3K4 is required for nucleosome deposition, histone turnover and chromatin remodeler binding at regulatory regions, where tight regulation of Pol II activity is necessary for proper ESC differentiation.
Keywords:	Alanine, Cell Differentiation, Chromatin Assembly and Disassembly, Genetic Enhancer Elements, Genetic Promoter Regions, Genetic Transcription, HEK293 Cells, Histone Code, Histones, Lysine, Mouse Embryonic Stem Cells, Mutation, Nucleic Acid Regulatory Sequences, Nucleosomes, RNA Polymerase II, Animals, Mice
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	52
Number:	3
Page Range:	273-282
Date:	March 2020
Official Publication:	https://doi.org/10.1038/s41588-020-0586-5
PubMed:	View item in PubMed

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