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

Autor: Yusufova N; Division of Hematology and Medical Oncology, Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.; Cell and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY, USA., Kloetgen A; Department of Pathology, NYU School of Medicine, New York, NY, USA.; Department of Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Braunschweig, Germany., Teater M; Division of Hematology and Medical Oncology, Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Osunsade A; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA., Camarillo JM; Department of Chemistry, Northwestern University, Evanston, IL, USA.; Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.; Proteomics Center of Excellence, Northwestern University, Evanston, IL, USA., Chin CR; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.; Tri-Institutional PhD Program in Computational Biomedicine, New York, NY, USA., Doane AS; Tri-Institutional PhD Program in Computational Biomedicine, New York, NY, USA.; Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA., Venters BJ; EpiCypher, Durham, NC, USA., Portillo-Ledesma S; Department of Chemistry, New York University, New York, NY, USA., Conway J; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., Phillip JM; Division of Hematology and Medical Oncology, Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Elemento O; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA., Scott DW; Centre for Lymphoid Cancer, BC Cancer, Vancouver, British Columbia, Canada., Béguelin W; Division of Hematology and Medical Oncology, Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Licht JD; University of Florida Health Cancer Center, The University of Florida Cancer and Genetics Research Complex, Gainesville, FL, USA., Kelleher NL; Department of Chemistry, Northwestern University, Evanston, IL, USA.; Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.; Proteomics Center of Excellence, Northwestern University, Evanston, IL, USA., Staudt LM; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Skoultchi AI; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA., Keogh MC; EpiCypher, Durham, NC, USA., Apostolou E; Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Mason CE; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.; The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA.; The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA., Imielinski M; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., Schlick T; Department of Chemistry, New York University, New York, NY, USA.; Courant Institute of Mathematical Sciences, New York University, New York, NY, USA.; New York University-East China Normal University Center for Computational Chemistry at New York University Shanghai, Shanghai, China., David Y; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA., Tsirigos A; Department of Pathology, NYU School of Medicine, New York, NY, USA.; Institute for Computational Medicine, NYU School of Medicine, New York, NY, USA., Allis CD; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA., Soshnev AA; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA. asoshnev@rockefeller.edu., Cesarman E; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. ecesarm@med.cornell.edu., Melnick AM; Division of Hematology and Medical Oncology, Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA. amm2014@med.cornell.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Jan; Vol. 589 (7841), pp. 299-305. Date of Electronic Publication: 2020 Dec 09.
DOI: 10.1038/s41586-020-3017-y
Abstrakt: Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction 1 , 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.
Databáze: MEDLINE
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