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 Apostolou, Christopher E. Mason, Marcin Imielinski, Tamar Schlick, Yael David, Aristotelis Tsirigos, C. David Allis, Alexey A. Soshnev (), Ethel Cesarman () and Ari M. Melnick ()
Additional contact information
Nevin Yusufova: Weill Cornell Medicine
Andreas Kloetgen: NYU School of Medicine
Matt Teater: Weill Cornell Medicine
Adewola Osunsade: Memorial Sloan Kettering Cancer Center
Jeannie M. Camarillo: Northwestern University
Christopher R. Chin: Weill Cornell Medicine
Ashley S. Doane: Tri-Institutional PhD Program in Computational Biomedicine
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
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
Christopher E. Mason: Weill Cornell Medicine
Marcin Imielinski: Weill Cornell Medicine
Tamar Schlick: New York University
Yael David: Memorial Sloan Kettering Cancer Center
Aristotelis Tsirigos: 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

Nature, 2021, vol. 589, issue 7841, 299-305

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (5)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-3017-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:589:y:2021:i:7841:d:10.1038_s41586-020-3017-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-3017-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().