Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture.

TitleHistone H1 loss drives lymphoma by disrupting 3D chromatin architecture.
Publication TypeJournal Article
Year of Publication2021
AuthorsYusufova N, Kloetgen A, Teater M, Osunsade A, Camarillo JM, Chin CR, Doane AS, Venters BJ, Portillo-Ledesma S, Conway J, Phillip JM, Elemento O, Scott DW, Béguelin W, Licht JD, Kelleher NL, Staudt LM, Skoultchi AI, Keogh M-C, Apostolou E, Mason CE, Imielinski M, Schlick T, David Y, Tsirigos A, C Allis D, Soshnev AA, Cesarman E, Melnick AM
JournalNature
Volume589
Issue7841
Pagination299-305
Date Published2021 01
ISSN1476-4687
KeywordsAlleles, Animals, B-Lymphocytes, Cell Self Renewal, Cell Transformation, Neoplastic, Chromatin, Chromatin Assembly and Disassembly, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, Tumor Suppressor, Germinal Center, Histones, Humans, Lymphoma, Mice, Mutation, Stem Cells
Abstract

Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction, 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.

DOI10.1038/s41586-020-3017-y
Alternate JournalNature
PubMed ID33299181
PubMed Central IDPMC7855728
Grant ListP01 CA196539 / CA / NCI NIH HHS / United States
P41 GM108569 / GM / NIGMS NIH HHS / United States
R01 CA234561 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
P30 CA060553 / CA / NCI NIH HHS / United States
R35 GM138386 / GM / NIGMS NIH HHS / United States
R01 CA195732 / CA / NCI NIH HHS / United States
S10 OD025194 / OD / NIH HHS / United States
U54 CA193419 / CA / NCI NIH HHS / United States
R44 DE029633 / DE / NIDCR NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
P01 CA229086 / CA / NCI NIH HHS / United States
R35 GM122562 / GM / NIGMS NIH HHS / United States
R01 CA228528 / CA / NCI NIH HHS / United States
R01 GM116143 / GM / NIGMS NIH HHS / United States
R44 GM116584 / GM / NIGMS NIH HHS / United States
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Ethel Cesarman, M.D., Ph.D. Marcin Imielinski, M.D., Ph.D.

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