title: The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells.
abstract: Epigenetic regulation of lineage-specific genes is important for the differentiation and function of T cells. Ten-eleven translocation (Tet) proteins catalyze 5-methylcytosine (5 mC) conversion to 5-hydroxymethylcytosine (5 hmC) to mediate DNA demethylation. However, the roles of Tet proteins in the immune response are unknown. Here, we characterized the genome-wide distribution of 5 hmC in CD4(+) T cells and found that 5 hmC marks putative regulatory elements in signature genes associated with effector cell differentiation. Moreover, Tet2 protein was recruited to 5 hmC-containing regions, dependent on lineage-specific transcription factors. Deletion of Tet2 in T cells decreased their cytokine expression, associated with reduced p300 recruitment. In vivo, Tet2 plays a critical role in the control of cytokine gene expression in autoimmune disease. Collectively, our findings suggest that Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells.
authors: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Kenji
authors: K
authors: Ichiyama
authors: State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510275, China.
authors: Tingting
authors: T
authors: Chen
authors: Institute for Immunology, Tsinghua University, Beijing 100084, China.
authors: Xiaohu
authors: X
authors: Wang
authors: Institute for Systems Biology, Seattle, WA 98109, USA.
authors: Xiaowei
authors: X
authors: Yan
authors: Department of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA.
authors: Byung-Seok
authors: BS
authors: Kim
authors: Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors: Shinya
authors: S
authors: Tanaka
authors: Howard Hughes Medical Institute and Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors: Delphine
authors: D
authors: Ndiaye-Lobry
authors: State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510275, China.
authors: Yuhua
authors: Y
authors: Deng
authors: State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510275, China.
authors: Yanli
authors: Y
authors: Zou
authors: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Pan
authors: P
authors: Zheng
authors: Institute for Systems Biology, Seattle, WA 98109, USA.
authors: Qiang
authors: Q
authors: Tian
authors: Howard Hughes Medical Institute and Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors: Iannis
authors: I
authors: Aifantis
authors: State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510275, China. Electronic address: weil9@mail.sysu.edu.cn.
authors: Lai
authors: L
authors: Wei
authors: Institute for Immunology, Tsinghua University, Beijing 100084, China. Electronic address: chendong@tsinghua.edu.cn.
authors: Chen
authors: C
authors: Dong
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D003596:Cytosine / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D049308:Dioxygenases; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000276:immunology; D044127:Epigenesis, Genetic / Q000276:immunology*; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D004247:DNA; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse