Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development
S. Haihua Chu,
Jonathan R. Chabon,
Chloe N. Matovina,
Janna C. Minehart,
Bo-Ruei Chen,
Jian Zhang,
Vipul Kumar,
Yijun Xiong,
Elsa Callen,
Putzer J. Hung,
Zhaohui Feng,
Richard P. Koche,
X. Shirley Liu,
Jayanta Chaudhuri,
Andre Nussenzweig,
Barry P. Sleckman,
Scott A. Armstrong
Affiliations
S. Haihua Chu
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
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
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
New York University School of Medicine, New York, NY, USA
Bo-Ruei Chen
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
Jian Zhang
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
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
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
Laboratory of Genome Integrity, National Cancer Institute National Institutes of Health, Bethesda, MD, USA
Putzer J. Hung
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
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
Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
X. Shirley Liu
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA
Jayanta Chaudhuri
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
Laboratory of Genome Integrity, National Cancer Institute National Institutes of Health, Bethesda, MD, USA
Barry P. Sleckman
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
Scott A. Armstrong
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; Corresponding author
Summary: 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. : Biological Sciences; Molecular Biology; Immunology; Cell Biology Subject Areas: Biological Sciences, Molecular Biology, Immunology, Cell Biology
