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.

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*
  • 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
  • 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-box transcription factor TBX21
  • Tet2 protein, mouse
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine
  • DNA
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse

Associated data

  • GEO/GSE66268
  • GEO/GSE66944