Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture

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 M. Phillip, Olivier Elemento, David W. Scott, Wendy Béguelin, Jonathan D. Licht, Neil L. Kelleher, Louis M. Staudt, Arthur I. Skoultchi, Michael Christopher Keogh, Effie ApostolouChristopher E. Mason, Marcin Imielinski, Tamar Schlick, Yael David, Aristotelis Tsirigos, C. David Allis, Alexey A. Soshnev*, Ethel Cesarman*, Ari M. Melnick*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

164 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)299-305
Number of pages7
JournalNature
Volume589
Issue number7841
DOIs
StatePublished - Jan 14 2021

Funding

Acknowledgements E.C., A.M.M. and C.D.A. are funded through NIH/NCI R01 CA234561 and STARR I9-A9-062. A.M.M. and A.T. are funded by NIH/NCI P01 CA229086. Research in the C.D.A. laboratory is also supported by the NCI P01 CA196539 Leukemia and Lymphoma Society (LLS-SCOR 7006-13), The Rockefeller University and St Jude Children’s Research Hospital Collaborative on Chromatin Regulation in Pediatric Cancer and Robertson Therapeutic Development Fund. A.M.M. is also funded by NIH/NCI R35 CA220499, LLS TRP 6572, LLS SCOR 7012, the Follicular Lymphoma Consortium, the Samuel Waxman Cancer Research Foundation and the Chemotherapy Foundation. J.D.L., A.M.M. and C.D.A. are funded by LLS SCOR 17403-19 and J.D.L. is funded by R01 CA195732 and The Samuel Waxman Cancer Research Foundation. N.Y. is funded by the Congressionally Directed Medical Research Program (CA181397). Research in EpiCypher is supported by R44 DE029633 and R44 GM116584. A.A.S. was funded by the Damon Runyon Cancer Research Foundation (DRG-2185-14). A.I.S. is funded through GM116143. Histone proteomics work was performed at Northwestern Proteomics, which was supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, an instrumentation award (S10OD025194) from the NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. The in silico modelling work was supported by award R35-GM122562 to T.S. The authors thank the Laboratory of Comparative Pathology, Epigenomics Core, Flow Cytometry Core Facility and Optical Microscopy Core at Weill Cornell Medicine; the Genomics Resource Center and Bio-Imaging Resource Center at The Rockefeller University; and Langone Health’s Genome Technology Center at New York University.

ASJC Scopus subject areas

  • General

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