E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment

Blood. 2013 Feb 28;121(9):1534-42. doi: 10.1182/blood-2012-08-449447. Epub 2013 Jan 7.

Abstract

The E2A transcription factors promote the development of thymus-seeding cells, but it remains unknown whether these proteins play a role in T lymphocyte lineage specification or commitment. Here, we showed that E2A proteins were required to promote T-lymphocyte commitment from DN2 thymocytes and to extinguish their potential for alternative fates. E2A proteins functioned in DN2 cells to limit expression of Gata3, which encodes an essential T-lymphocyte transcription factor whose ectopic expression can arrest T-cell differentiation. Genetic, or small interfering RNA-mediated, reduction of Gata3 rescued T-cell differentiation in the absence of E2A and restricted the development of alternative lineages by limiting the expanded self-renewal potential in E2A−/− DN2 cells. Our data support a novel paradigm in lymphocyte lineage commitment in which the E2A proteins are necessary to limit the expression of an essential lineage specification and commitment factor to restrain self-renewal and to prevent an arrest in differentiation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Cell Differentiation / genetics*
  • Cell Lineage / genetics*
  • Cells, Cultured
  • Down-Regulation
  • GATA3 Transcription Factor / genetics*
  • GATA3 Transcription Factor / metabolism
  • GATA3 Transcription Factor / physiology
  • Gene Expression Regulation
  • Hematopoiesis / genetics
  • Hematopoiesis / immunology
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / physiology
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / physiology
  • Mice
  • Mice, Transgenic
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / physiology*
  • Thymocytes / metabolism
  • Thymocytes / physiology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Tcf3 protein, mouse