@article{a5f2af111cfe4271a4460d0841ca789b,
title = "Lysine 4 of histone H3.3 is required for embryonic stem cell differentiation, histone enrichment at regulatory regions and transcription accuracy",
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.",
author = "Maja Gehre and Daria Bunina and Simone Sidoli and L{\"u}bke, {Marlena J.} and Nichole Diaz and Matteo Trovato and Garcia, {Benjamin A.} and Zaugg, {Judith B.} and Noh, {Kyung Min}",
note = "Funding Information: We thank the staff at the EMBL Genomics Core Facility, the Flow Cytometry Core Facility, the Proteomics Core Facility and the Advanced Light Microscopy Facility for sample preparation and data generation. We thank C. Girardot and the Genome Biology Computational Support for their assistance in data analysis, N. Arecco for establishing the PRO-seq experiment, A. Hill for help with image analysis and E. Furlong and the Noh laboratory for revising the manuscript and for helpful discussions. This work is supported by the DFG fund (no. SPP 1738-NO 1249 to K.M.N.) and the EMBL Interdisciplinary Postdoc (EI3POD) fellowship under Marie Sk{\l}odowska-Curie Actions COFUND (no. 664726 to D.B.). S.S. and B.A.G. gratefully acknowledge National Institutes of Helth grant nos. CA196539, GM110174 and AI118891. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = mar,
day = "1",
doi = "10.1038/s41588-020-0586-5",
language = "English",
volume = "52",
pages = "273--282",
journal = "Nature Genetics",
issn = "1061-4036",
number = "3",
}