Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development.

Biological Sciences Cell Biology Immunology Molecular Biology

Journal

iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038

Informations de publication

Date de publication:
27 Mar 2020
Historique:
received: 07 10 2019
revised: 25 01 2020
accepted: 21 02 2020
pubmed: 15 3 2020
medline: 15 3 2020
entrez: 15 3 2020
Statut: ppublish

Résumé

Repair of DNA double-stranded breaks (DSBs) during lymphocyte development is essential for V(D)J recombination and forms the basis of immunoglobulin variable region diversity. Understanding of this process in lymphogenesis has historically been centered on the study of RAG1/2 recombinases and a set of classical non-homologous end-joining factors. Much less has been reported regarding the role of chromatin modifications on this process. Here, we show a role for the non-redundant histone H3 lysine methyltransferase, Setd2, and its modification of lysine-36 trimethylation (H3K36me3), in the processing and joining of DNA ends during V(D)J recombination. Loss leads to mis-repair of Rag-induced DNA DSBs, especially when combined with loss of Atm kinase activity. Furthermore, loss reduces immune repertoire and a severe block in lymphogenesis as well as causes post-mitotic neuronal apoptosis. Together, these studies are suggestive of an important role of Setd2/H3K36me3 in these two mammalian developmental processes that are influenced by double-stranded break repair.

Identifiants

DOI: 10.1016/j.isci.2020.100941 PMID: 32169821 PMC: PMC7066224
pubmed: 32169821
pii: S2589-0042(20)30125-5
doi: 10.1016/j.isci.2020.100941
pmc: PMC7066224
pii:
doi:

Types de publication

Journal Article

Langues

eng

Pagination

100941

Subventions

Organisme : NIAID NIH HHS
ID : R01 AI047829
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA066996
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA176745
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI074953
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA189740
Pays : United States

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests S.A.A. has been a consultant and/or shareholder for Epizyme Inc, Imago Biosciences, Cyteir Therapeutics, C4 Therapeutics, Syros Pharmaceuticals, OxStem Oncology, Accent Therapeutics, and Mana Therapeutics. S.A.A. has received research support from Janssen, Novartis, and AstraZeneca. S.H.C. is currently an employee at Beam Therapeutics. The authors have no additional financial interests.

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Auteurs

S Haihua Chu (SH)

Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, 450 Brookline Avenue, Boston, MA 02215-5450, USA.

Jonathan R Chabon (JR)

Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, 450 Brookline Avenue, Boston, MA 02215-5450, USA.

Chloe N Matovina (CN)

Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, 450 Brookline Avenue, Boston, MA 02215-5450, USA.

Janna C Minehart (JC)

New York University School of Medicine, New York, NY, USA.

Bo-Ruei Chen (BR)

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.

Jian Zhang (J)

Center for Computational Biology, Beijing Institute of Basic Medical Sciences, Beijing, China; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Vipul Kumar (V)

Howard Hughes Medical Institute, Department of Pediatrics, Department of Genetics, Harvard Medical School, Boston, MA, USA; Harvard-MIT MD-PhD Program, Harvard Medical School, Boston, MA, USA.

Yijun Xiong (Y)

Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, 450 Brookline Avenue, Boston, MA 02215-5450, USA.

Elsa Callen (E)

Laboratory of Genome Integrity, National Cancer Institute National Institutes of Health, Bethesda, MD, USA.

Putzer J Hung (PJ)

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.

Zhaohui Feng (Z)

Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, 450 Brookline Avenue, Boston, MA 02215-5450, USA.

Richard P Koche (RP)

Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

X Shirley Liu (XS)

Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Jayanta Chaudhuri (J)

Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.

Andre Nussenzweig (A)

Laboratory of Genome Integrity, National Cancer Institute National Institutes of Health, Bethesda, MD, USA.

Barry P Sleckman (BP)

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.

Scott A Armstrong (SA)

Department of Pediatric Oncology, Dana Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, 450 Brookline Avenue, Boston, MA 02215-5450, USA. Electronic address: scott_armstrong@dfci.harvard.edu.

Classifications MeSH