한빛사논문
- 조회3,179
Abstract
Semir Beyaz1,2,9, Ji Hyung Kim3,9, Luca Pinello4,9, Michael E Xifaras5, Yu Hu3, Jialiang Huang4, Marc A Kerenyi1,2,6, Partha P Das1,2, R Anthony Barnitz1,7, Aurelie Herault8, Rizkullah Dogum5, W Nicholas Haining1,7, Omer H Yilmaz5, Emmanuelle Passegue8, Guo-Cheng Yuan4, Stuart H Orkin1,2,10 & Florian Winau3,10
1Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA. 3Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA. 4Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA, and Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 5The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 6Department of Pharmacology and Translational Research, Boehringer Ingelheim, Vienna, Austria. 7Department of Pediatric Oncology, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Cambridge, USA. 8The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, USA, and Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California, USA. 9These authors contributed equally to this work. 10These authors jointly directed this work.
Correspondence to : Stuart H Orkin or Florian Winau
Abstract
Invariant natural killer T cells (iNKT cells) are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about the epigenetic regulation of iNKT cell development. Here we found that the H3K27me3 histone demethylase UTX was an essential cell-intrinsic factor that controlled an iNKT-cell lineage-specific gene-expression program and epigenetic landscape in a demethylase-activity-dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT cell signature genes due to a decrease in activation-associated H3K4me3 marks and an increase in repressive H3K27me3 marks within the promoters occupied by UTX. We found that JunB regulated iNKT cell development and that the expression of genes that were targets of both JunB and the iNKT cell master transcription factor PLZF was UTX dependent. We identified iNKT cell super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for commitment to the iNKT cell lineage. Our findings reveal how UTX regulates the development of iNKT cells through multiple epigenetic mechanisms.
논문정보
- Research article
- 2016년 12월 (BRIC 등록일 2016-12-23)
- 국외 연구진
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