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TitleH1 histones control the epigenetic landscape by local chromatin compaction.
Publication TypeJournal Article
Year of Publication2021
AuthorsWillcockson, Michael A., Healton Sean E., Weiss Cary N., Bartholdy Boris A., Botbol Yair, Mishra Laxmi N., Sidhwani Dhruv S., Wilson Tommy J., Pinto Hugo B., Maron Maxim I., Skalina Karin A., Toro Laura Norwood, Zhao Jie, Lee Chul-Hwan, Hou Harry, Yusufova Nevin, Meydan Cem, Osunsade Adewola, David Yael, Cesarman Ethel, Melnick Ari M., Sidoli Simone, Garcia Benjamin A., Edelmann Winfried, Macian Fernando, and Skoultchi Arthur I.
JournalNature
Volume589
Issue7841
Pagination293-298
Date Published2021 01
ISSN1476-4687
KeywordsAnimals, CD8-Positive T-Lymphocytes, Cell Differentiation, Chromatin, Chromatin Assembly and Disassembly, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Female, Gene Silencing, Histones, Lymphocyte Activation, Male, Methylation, Mice, Mice, Knockout
Abstract

<p>H1 linker histones are the most abundant chromatin-binding proteins. In vitro studies indicate that their association with chromatin determines nucleosome spacing and enables arrays of nucleosomes to fold into more compact chromatin structures. However, the in vivo roles of H1 are poorly understood. Here we show that the local density of H1 controls the balance of repressive and active chromatin domains by promoting genomic compaction. We generated a conditional triple-H1-knockout mouse strain and depleted H1 in haematopoietic cells. H1 depletion in T cells leads to de-repression of T cell activation genes, a process that mimics normal T cell activation. Comparison of chromatin structure in normal and H1-depleted CD8 T cells reveals that H1-mediated chromatin compaction occurs primarily in regions of the genome containing higher than average levels of H1: the chromosome conformation capture (Hi-C) B compartment and regions of the Hi-C A compartment marked by PRC2. Reduction of H1 stoichiometry leads to decreased H3K27 methylation, increased H3K36 methylation, B-to-A-compartment shifting and an increase in interaction frequency between compartments. In vitro, H1 promotes PRC2-mediated H3K27 methylation and inhibits NSD2-mediated H3K36 methylation. Mechanistically, H1 mediates these opposite effects by promoting physical compaction of the chromatin substrate. Our results establish H1 as a critical regulator of gene silencing through localized control of chromatin compaction, 3D genome organization and the epigenetic landscape.</p>

DOI10.1038/s41586-020-3032-z
Alternate JournalNature
PubMed ID33299182
PubMed Central IDPMC8110206
Grant ListGM110104 / NH / NIH HHS / United States
AI118891 / NH / NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 AI118891 / AI / NIAID NIH HHS / United States
F30 DK107182 / DK / NIDDK NIH HHS / United States
T32 GM007288 / GM / NIGMS NIH HHS / United States
R01 CA226861 / CA / NCI NIH HHS / United States
P30 CA013330 / CA / NCI NIH HHS / United States
R01 GM116143 / GM / NIGMS NIH HHS / United States
F30 CA210539 / CA / NCI NIH HHS / United States
R01 CA234561 / CA / NCI NIH HHS / United States
R01 GM129244 / GM / NIGMS NIH HHS / United States
R35 GM138386 / GM / NIGMS NIH HHS / United States
F30 DK108532 / DK / NIDDK NIH HHS / United States