title: The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells.
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.
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Semir
authors.identifier: 0000-0003-4730-4012
authors.initials: S
authors.lastname: Beyaz
authors.affiliation: Program 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.
authors.forename: Ji Hyung
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA, and Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Xifaras
authors.affiliation: Program 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.
authors.forename: Yu
authors.identifier: 0000-0002-9511-9383
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA, and Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Huang
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pharmacology and Translational Research, Boehringer Ingelheim, Vienna, Austria.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Kerenyi
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Partha P
authors.initials: PP
authors.lastname: Das
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Cambridge, USA.
authors.forename: R Anthony
authors.initials: RA
authors.lastname: Barnitz
authors.affiliation: The 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.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Herault
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Rizkullah
authors.initials: R
authors.lastname: Dogum
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Cambridge, USA.
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Ömer H
authors.initials: ÖH
authors.lastname: Yilmaz
authors.affiliation: The 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.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegue
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA, and Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Program 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.
authors.forename: Florian
authors.initials: F
authors.lastname: Winau
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000502:physiology*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C584097:JunB protein, mouse; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D014157:Transcription Factors; C513267:Zbtb16 protein, mouse; D056466:Histone Demethylases; C111778:Utx protein, mouse