T-cell receptor α enhancer is inactivated in αβ T lymphocytes

Proc Natl Acad Sci U S A. 2015 Apr 7;112(14):E1744-53. doi: 10.1073/pnas.1406551112. Epub 2015 Mar 23.

Abstract

The Tcra enhancer (Eα) is essential for Tcra locus germ-line transcription and primary Vα-to-Jα recombination during thymocyte development. We found that Eα is inhibited late during thymocyte differentiation and in αβ T lymphocytes, indicating that it is not required to drive transcription of rearranged Tcra genes. Eα inactivation resulted in the disruption of functional long-range enhancer-promoter interactions and was associated with loss of Eα-dependent histone modifications at promoter and enhancer regions, and reduced expression and recruitment of E2A to the Eα enhanceosome in T cells. Enhancer activity could not be recovered by T-cell activation, by forced expression of E2A or by the up-regulation of this and other transcription factors in the context of T helper differentiation. Our results argue that the major function of Eα is to coordinate the formation of a chromatin hub that drives Vα and Jα germ-line transcription and primary rearrangements in thymocytes and imply the existence of an Eα-independent mechanism to activate transcription of the rearranged Tcra locus in αβ T cells.

Keywords: T-cell development; T-cell receptor; enhancer; transcription.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Separation
  • Chromatin / metabolism
  • Enhancer Elements, Genetic*
  • Exons
  • Flow Cytometry
  • Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor*
  • Histones / chemistry
  • Mice
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell, alpha-beta / genetics*
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • T-Lymphocytes / cytology*
  • T-Lymphocytes, Helper-Inducer / cytology
  • Thymocytes / cytology
  • Transcription, Genetic
  • Transcriptional Activation
  • Up-Regulation

Substances

  • Chromatin
  • Histones
  • Receptors, Antigen, T-Cell, alpha-beta