The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells

Kenji Ichiyama; Tingting Chen; Xiaohu Wang; Xiaowei Yan; Byung-Seok Kim; Shinya Tanaka; Delphine Ndiaye-Lobry; Yuhua Deng; Yanli Zou; Pan Zheng; Qiang Tian; Iannis Aifantis; Lai Wei; Chen Dong

doi:10.1016/j.immuni.2015.03.005

The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells

Immunity. 2015 Apr 21;42(4):613-26. doi: 10.1016/j.immuni.2015.03.005. Epub 2015 Apr 7.

Authors

Kenji Ichiyama¹, Tingting Chen², Xiaohu Wang³, Xiaowei Yan⁴, Byung-Seok Kim⁵, Shinya Tanaka⁶, Delphine Ndiaye-Lobry⁷, Yuhua Deng², Yanli Zou², Pan Zheng¹, Qiang Tian⁴, Iannis Aifantis⁷, Lai Wei⁸, Chen Dong⁹

Affiliations

¹ Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA.
² State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510275, China.
³ Institute for Immunology, Tsinghua University, Beijing 100084, China.
⁴ Institute for Systems Biology, Seattle, WA 98109, USA.
⁵ Department of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA.
⁶ Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
⁷ Howard Hughes Medical Institute and Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
⁸ State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510275, China. Electronic address: [email protected].
⁹ Institute for Immunology, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

5-Methylcytosine / analogs & derivatives
Animals
Cell Differentiation
Cytokines / biosynthesis*
Cytokines / immunology
Cytosine / analogs & derivatives
Cytosine / immunology
Cytosine / metabolism
DNA / immunology
DNA / metabolism
DNA Methylation
DNA-Binding Proteins / genetics
DNA-Binding Proteins / immunology*
Dioxygenases
E1A-Associated p300 Protein / genetics
E1A-Associated p300 Protein / immunology
Epigenesis, Genetic / immunology*
Gene Expression Regulation
Genome
Humans
Mice
Mice, Transgenic
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / immunology*
STAT4 Transcription Factor / genetics
STAT4 Transcription Factor / immunology
T-Box Domain Proteins / genetics
T-Box Domain Proteins / immunology
T-bet Transcription Factor
Th1 Cells / cytology
Th1 Cells / enzymology
Th1 Cells / immunology*
Th17 Cells / cytology
Th17 Cells / enzymology
Th17 Cells / immunology*

Substances

Cytokines
DNA-Binding Proteins
Proto-Oncogene Proteins
STAT4 Transcription Factor
Stat4 protein, mouse
T-Box Domain Proteins
T-bet Transcription Factor
5-hydroxymethylcytosine
5-Methylcytosine
Cytosine
DNA
Dioxygenases
Tet2 protein, mouse
E1A-Associated p300 Protein
Ep300 protein, mouse

Associated data

GEO/GSE66268
GEO/GSE66944

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding