Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility

Elife. 2016 Nov 21;5:e18290. doi: 10.7554/eLife.18290.

Abstract

Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine, facilitating DNA demethylation and generating new epigenetic marks. Here we show that concomitant loss of Tet2 and Tet3 in mice at early B cell stage blocked the pro- to pre-B cell transition in the bone marrow, decreased Irf4 expression and impaired the germline transcription and rearrangement of the Igκ locus. Tet2/3-deficient pro-B cells showed increased CpG methylation at the Igκ 3' and distal enhancers that was mimicked by depletion of E2A or PU.1, as well as a global decrease in chromatin accessibility at enhancers. Importantly, re-expression of the Tet2 catalytic domain in Tet2/3-deficient B cells resulted in demethylation of the Igκ enhancers and restored their chromatin accessibility. Our data suggest that TET proteins and lineage-specific transcription factors cooperate to influence chromatin accessibility and Igκ enhancer function by modulating the modification status of DNA.

Keywords: 5hmC; B cell development; DNA methylation; Tet proteins; chromosomes; genes; immunology; mouse.

MeSH terms

  • 5-Methylcytosine / metabolism
  • Animals
  • B-Lymphocytes / physiology*
  • Cell Differentiation
  • Chromatin / metabolism*
  • DNA / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • Interferon Regulatory Factors / metabolism*
  • Mice
  • Proto-Oncogene Proteins / metabolism*
  • Transcription, Genetic*

Substances

  • Chromatin
  • DNA-Binding Proteins
  • Interferon Regulatory Factors
  • Proto-Oncogene Proteins
  • Tet2 protein, mouse
  • interferon regulatory factor-4
  • 5-Methylcytosine
  • DNA
  • Tet3 protein, mouse