@article{655d3f73cc1b468c82f55036a9c4b7a7,
title = "H1 histones control the epigenetic landscape by local chromatin compaction",
abstract = "H1 linker histones are the most abundant chromatin-binding proteins1. 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 understood2. 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.",
author = "Willcockson, {Michael A.} and Healton, {Sean E.} and Weiss, {Cary N.} and Bartholdy, {Boris A.} and Yair Botbol and Mishra, {Laxmi N.} and Sidhwani, {Dhruv S.} and Wilson, {Tommy J.} and Pinto, {Hugo B.} and Maron, {Maxim I.} and Skalina, {Karin A.} and Toro, {Laura Norwood} and Jie Zhao and Lee, {Chul Hwan} and Harry Hou and Nevin Yusufova and Cem Meydan and Adewola Osunsade and Yael David and Ethel Cesarman and Melnick, {Ari M.} and Simone Sidoli and Garcia, {Benjamin A.} and Winfried Edelmann and Fernando Macian and Skoultchi, {Arthur I.}",
note = "Funding Information: Acknowledgements We thank the Albert Einstein College of Medicine Analytical Imaging Facility for their assistance in preparing samples for transmission electron microscopy and acquiring images, and the Flow Cytometry Core Facility (NCI P30CA013330). We thank D. Reinberg for preparations of the PRC2–AEBP complex; M. Gamble, C. Query and all members of the Skoultchi laboratory for stimulating scientific discussions; G. Yu, B. Will, K. Gritsman, A. Emelyanov, D. Fyodorov and M. Scharff for reagents and expert advice. This work was supported in part by funds from the NIGMS (R01GM116143 to A.I.S.; GM110104 to B.A.G.), the National Cancer Institute (F30CA210539 to S.E.H.; CA196539 to B.A.G.) and the National Institute of Diabetes and Digestive and Kidney Diseases (F30DK108532 to C.N.W.; F30DK107182 to M.A.W.) and the National Institute of Allergy and Infectious Disease (AI118891 to B.A.G.). E.C. and A.M.M. are funded through NIH/NCI R01 CA234561 and STARR I9-A9-062. In addition, this work is supported by an NIH, NIGMS MSTP Training Grant T32GM007288 (S.E.H., C.N.W. and M.A.W., under M. Akabas (programme director)). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2021",
month = jan,
day = "14",
doi = "10.1038/s41586-020-3032-z",
language = "English",
volume = "589",
pages = "293--298",
journal = "Nature",
issn = "0028-0836",
number = "7841",
}