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Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture

Author

Listed:
  • Nevin Yusufova

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Andreas Kloetgen

    (NYU School of Medicine
    Helmholtz Centre for Infection Research)

  • Matt Teater

    (Weill Cornell Medicine)

  • Adewola Osunsade

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

  • Jeannie M. Camarillo

    (Northwestern University
    Northwestern University
    Northwestern University)

  • Christopher R. Chin

    (Weill Cornell Medicine
    Tri-Institutional PhD Program in Computational Biomedicine)

  • Ashley S. Doane

    (Tri-Institutional PhD Program in Computational Biomedicine
    Weill Cornell Medicine)

  • Bryan J. Venters

    (EpiCypher)

  • Stephanie Portillo-Ledesma

    (New York University)

  • Joseph Conway

    (Weill Cornell Medicine)

  • Jude M. Phillip

    (Weill Cornell Medicine)

  • Olivier Elemento

    (Weill Cornell Medicine)

  • David W. Scott

    (Centre for Lymphoid Cancer, BC Cancer)

  • Wendy Béguelin

    (Weill Cornell Medicine)

  • Jonathan D. Licht

    (The University of Florida Cancer and Genetics Research Complex)

  • Neil L. Kelleher

    (Northwestern University
    Northwestern University
    Northwestern University)

  • Louis M. Staudt

    (National Cancer Institute, National Institutes of Health)

  • Arthur I. Skoultchi

    (Albert Einstein College of Medicine)

  • Michael-Christopher Keogh

    (EpiCypher)

  • Effie Apostolou

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Christopher E. Mason

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Marcin Imielinski

    (Weill Cornell Medicine)

  • Tamar Schlick

    (New York University
    New York University
    New York University–East China Normal University Center for Computational Chemistry at New York University Shanghai)

  • Yael David

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

  • Aristotelis Tsirigos

    (NYU School of Medicine
    NYU School of Medicine)

  • C. David Allis

    (The Rockefeller University)

  • Alexey A. Soshnev

    (The Rockefeller University)

  • Ethel Cesarman

    (Weill Cornell Medicine)

  • Ari M. Melnick

    (Weill Cornell Medicine)

Abstract

Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction1, although their biological functions are poorly understood. Mutations in the genes that encode H1 isoforms B–E (H1B, H1C, H1D and H1E; also known as H1-5, H1-2, H1-3 and H1-4, respectively) are highly recurrent in B cell lymphomas, but the pathogenic relevance of these mutations to cancer and the mechanisms that are involved are unknown. Here we show that lymphoma-associated H1 alleles are genetic driver mutations in lymphomas. Disruption of H1 function results in a profound architectural remodelling of the genome, which is characterized by large-scale yet focal shifts of chromatin from a compacted to a relaxed state. This decompaction drives distinct changes in epigenetic states, primarily owing to a gain of histone H3 dimethylation at lysine 36 (H3K36me2) and/or loss of repressive H3 trimethylation at lysine 27 (H3K27me3). These changes unlock the expression of stem cell genes that are normally silenced during early development. In mice, loss of H1c and H1e (also known as H1f2 and H1f4, respectively) conferred germinal centre B cells with enhanced fitness and self-renewal properties, ultimately leading to aggressive lymphomas with an increased repopulating potential. Collectively, our data indicate that H1 proteins are normally required to sequester early developmental genes into architecturally inaccessible genomic compartments. We also establish H1 as a bona fide tumour suppressor and show that mutations in H1 drive malignant transformation primarily through three-dimensional genome reorganization, which leads to epigenetic reprogramming and derepression of developmentally silenced genes.

Suggested Citation

  • Nevin Yusufova & Andreas Kloetgen & Matt Teater & Adewola Osunsade & Jeannie M. Camarillo & Christopher R. Chin & Ashley S. Doane & Bryan J. Venters & Stephanie Portillo-Ledesma & Joseph Conway & Jude, 2021. "Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture," Nature, Nature, vol. 589(7841), pages 299-305, January.
  • Handle: RePEc:nat:nature:v:589:y:2021:i:7841:d:10.1038_s41586-020-3017-y
    DOI: 10.1038/s41586-020-3017-y
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    Citations

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    Cited by:

    1. 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.
    2. 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.
    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. 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.

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