CXXC finger protein 1 is critical for T-cell intrathymic development through regulating H3K4 trimethylation

Nat Commun. 2016 May 23;7:11687. doi: 10.1038/ncomms11687.

Abstract

T-cell development in the thymus is largely controlled by an epigenetic program, involving in both DNA methylation and histone modifications. Previous studies have identified Cxxc1 as a regulator of both cytosine methylation and histone 3 lysine 4 trimethylation (H3K4me3). However, it is unknown whether Cxxc1 plays a role in thymocyte development. Here we show that T-cell development in the thymus is severely impaired in Cxxc1-deficient mice. Furthermore, we identify genome-wide Cxxc1-binding sites and H3K4me3 modification sites in wild-type and Cxxc1-deficient thymocytes. Our results demonstrate that Cxxc1 directly controls the expression of key genes important for thymocyte survival such as RORγt and for T-cell receptor signalling including Zap70 and CD8, through maintaining the appropriate H3K4me3 on their promoters. Importantly, we show that RORγt, a direct target of Cxxc1, can rescue the survival defects in Cxxc1-deficient thymocytes. Our data strongly support a critical role of Cxxc1 in thymocyte development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8 Antigens / metabolism
  • Cell Line
  • Cell Survival
  • Epigenesis, Genetic
  • Histones / metabolism*
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • Thymocytes / physiology*
  • Trans-Activators / physiology*
  • ZAP-70 Protein-Tyrosine Kinase / metabolism

Substances

  • CD8 Antigens
  • Cxxc1 protein, mouse
  • Histones
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Antigen, T-Cell
  • Trans-Activators
  • histone H3 trimethyl Lys4
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse