Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T cell identity

Cell. 2012 Apr 13;149(2):467-82. doi: 10.1016/j.cell.2012.01.056.

Abstract

T cell development comprises a stepwise process of commitment from a multipotent precursor. To define molecular mechanisms controlling this progression, we probed five stages spanning the commitment process using RNA-seq and ChIP-seq to track genome-wide shifts in transcription, cohorts of active transcription factor genes, histone modifications at diverse classes of cis-regulatory elements, and binding repertoire of GATA-3 and PU.1, transcription factors with complementary roles in T cell development. The results highlight potential promoter-distal cis-regulatory elements in play and reveal both activation sites and diverse mechanisms of repression that silence genes used in alternative lineages. Histone marking is dynamic and reversible, and though permissive marks anticipate, repressive marks often lag behind changes in transcription. In vivo binding of PU.1 and GATA-3 relative to epigenetic marking reveals distinctive factor-specific rules for recruitment of these crucial transcription factors to different subsets of their potential sites, dependent on dose and developmental context.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation*
  • Epigenesis, Genetic*
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation
  • Genome-Wide Association Study
  • Histone Code
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Notch / metabolism
  • Regulatory Elements, Transcriptional
  • Signal Transduction
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / metabolism
  • Trans-Activators / metabolism
  • Transcription, Genetic

Substances

  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Proto-Oncogene Proteins
  • Receptors, Notch
  • Trans-Activators
  • proto-oncogene protein Spi-1

Associated data

  • GEO/GSE31235