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H1 histones control the epigenetic landscape by local chromatin compaction

Author

Listed:
  • Michael A. Willcockson

    (Albert Einstein College of Medicine)

  • Sean E. Healton

    (Albert Einstein College of Medicine)

  • Cary N. Weiss

    (Albert Einstein College of Medicine)

  • Boris A. Bartholdy

    (Albert Einstein College of Medicine)

  • Yair Botbol

    (Albert Einstein College of Medicine)

  • Laxmi N. Mishra

    (Albert Einstein College of Medicine)

  • Dhruv S. Sidhwani

    (Albert Einstein College of Medicine)

  • Tommy J. Wilson

    (Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York Presbyterian Hospital)

  • Hugo B. Pinto

    (Albert Einstein College of Medicine)

  • Maxim I. Maron

    (Albert Einstein College of Medicine)

  • Karin A. Skalina

    (Albert Einstein College of Medicine)

  • Laura Norwood Toro

    (Albert Einstein College of Medicine
    Medical College of Wisconsin)

  • Jie Zhao

    (Albert Einstein College of Medicine)

  • Chul-Hwan Lee

    (NYU School of Medicine
    Howard Hughes Medical Institute
    Seoul National University College of Medicine)

  • Harry Hou

    (Albert Einstein College of Medicine)

  • Nevin Yusufova

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Cem Meydan

    (Weill Cornell Medicine)

  • Adewola Osunsade

    (Memorial Sloan Kettering Cancer Center
    Tri-Institutional PhD Program in Chemical Biology)

  • Yael David

    (Memorial Sloan Kettering Cancer Center
    Tri-Institutional PhD Program in Chemical Biology)

  • Ethel Cesarman

    (Weill Cornell Medicine)

  • Ari M. Melnick

    (Weill Cornell Medicine)

  • Simone Sidoli

    (University of Pennsylvania, Smilow Center for Translational Research
    Albert Einstein College of Medicine)

  • Benjamin A. Garcia

    (University of Pennsylvania, Smilow Center for Translational Research)

  • Winfried Edelmann

    (Albert Einstein College of Medicine)

  • Fernando Macian

    (Albert Einstein College of Medicine)

  • Arthur I. Skoultchi

    (Albert Einstein College of Medicine)

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.

Suggested Citation

  • Michael A. Willcockson & Sean E. Healton & Cary N. Weiss & Boris A. Bartholdy & Yair Botbol & Laxmi N. Mishra & Dhruv S. Sidhwani & Tommy J. Wilson & Hugo B. Pinto & Maxim I. Maron & Karin A. Skalina , 2021. "H1 histones control the epigenetic landscape by local chromatin compaction," Nature, Nature, vol. 589(7841), pages 293-298, January.
  • Handle: RePEc:nat:nature:v:589:y:2021:i:7841:d:10.1038_s41586-020-3032-z
    DOI: 10.1038/s41586-020-3032-z
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    Citations

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    Cited by:

    1. Jingxuan Xu & Xiang Xu & Dandan Huang & Yawen Luo & Lin Lin & Xuemei Bai & Yang Zheng & Qian Yang & Yu Cheng & An Huang & Jingyi Shi & Xiaochen Bo & Jin Gu & Hebing Chen, 2024. "A comprehensive benchmarking with interpretation and operational guidance for the hierarchy of topologically associating domains," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Laura A. Murray-Nerger & Clarisel Lozano & Eric M. Burton & Yifei Liao & Nathan A. Ungerleider & Rui Guo & Benjamin E. Gewurz, 2024. "The nucleic acid binding protein SFPQ represses EBV lytic reactivation by promoting histone H1 expression," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Ko Sato & Amarjeet Kumar & Keisuke Hamada & Chikako Okada & Asako Oguni & Ayumi Machiyama & Shun Sakuraba & Tomohiro Nishizawa & Osamu Nureki & Hidetoshi Kono & Kazuhiro Ogata & Toru Sengoku, 2021. "Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    4. Yangmian Yuan & Yu Fan & Yihao Zhou & Rong Qiu & Wei Kang & Yu Liu & Yuchen Chen & Chenyu Wang & Jiajian Shi & Chengyu Liu & Yangkai Li & Min Wu & Kun Huang & Yong Liu & Ling Zheng, 2023. "Linker histone variant H1.2 is a brake on white adipose tissue browning," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Cuifang Liu & Juan Yu & Aoqun Song & Min Wang & Jiansen Hu & Ping Chen & Jicheng Zhao & Guohong Li, 2023. "Histone H1 facilitates restoration of H3K27me3 during DNA replication by chromatin compaction," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Rina Hirano & Haruhiko Ehara & Tomoya Kujirai & Tamami Uejima & Yoshimasa Takizawa & Shun-ichi Sekine & Hitoshi Kurumizaka, 2022. "Structural basis of RNA polymerase II transcription on the chromatosome containing linker histone H1," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    7. Tengfei Wang & Shuxiang Shi & Yuanyuan Shi & Peipei Jiang & Ganlu Hu & Qinying Ye & Zhan Shi & Kexin Yu & Chenguang Wang & Guoping Fan & Suwen Zhao & Hanhui Ma & Alex C. Y. Chang & Zhi Li & Qian Bian , 2023. "Chemical-induced phase transition and global conformational reorganization of chromatin," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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