Stage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development

Nat Commun. 2018 Sep 5;9(1):3594. doi: 10.1038/s41467-018-05834-w.

Abstract

The inheritance of gene expression patterns is dependent on epigenetic regulation, but the establishment and maintenance of epigenetic landscapes during T cell differentiation are incompletely understood. Here we show that two stage-specific Cd4 cis-elements, the previously characterized enhancer E4p and a novel enhancer E4m, coordinately promote Cd4 transcription in mature thymic MHC-II-specific T cells, in part through the canonical Wnt pathway. Specifically, E4p licenses E4m to orchestrate DNA demethylation by TET1 and TET3, which in turn poises the Cd4 locus for transcription in peripheral T cells. Cd4 locus demethylation is important for subsequent Cd4 transcription in activated peripheral T cells wherein these cis-elements become dispensable. By contrast, in developing thymocytes the loss of TET1/3 does not affect Cd4 transcription, highlighting an uncoupled event between transcription and epigenetic modifications. Together our findings reveal an important function for thymic cis-elements in governing gene expression in the periphery via a heritable epigenetic mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4 Antigens / genetics*
  • CD4 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / physiology*
  • Cell Differentiation / genetics
  • Chimera
  • DNA Demethylation
  • DNA Methylation / physiology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dioxygenases
  • Enhancer Elements, Genetic / physiology*
  • Epigenesis, Genetic / physiology*
  • Female
  • Gene Expression Regulation / physiology*
  • Gene Knockout Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / physiology

Substances

  • CD4 Antigens
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • Dioxygenases
  • Tet3 protein, mouse