The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations

Blood. 2014 Apr 24;123(17):e68-78. doi: 10.1182/blood-2013-02-486944. Epub 2014 Mar 26.

Abstract

CD4(+)CD25(+)FOXP3(+) human regulatory T cells (Tregs) are essential for self-tolerance and immune homeostasis. Here, we describe the promoterome of CD4(+)CD25(high)CD45RA(+) naïve and CD4(+)CD25(high)CD45RA(-) memory Tregs and their CD25(-) conventional T-cell (Tconv) counterparts both before and after in vitro expansion by cap analysis of gene expression (CAGE) adapted to single-molecule sequencing (HeliScopeCAGE). We performed comprehensive comparative digital gene expression analyses and revealed novel transcription start sites, of which several were validated as alternative promoters of known genes. For all in vitro expanded subsets, we additionally generated global maps of poised and active enhancer elements marked by histone H3 lysine 4 monomethylation and histone H3 lysine 27 acetylation, describe their cell type-specific motif signatures, and evaluate the role of candidate transcription factors STAT5, FOXP3, RUNX1, and ETS1 in both Treg- and Tconv-specific enhancer architectures. Network analyses of gene expression data revealed additional candidate transcription factors contributing to cell type specificity and a transcription factor network in Tregs that is dominated by FOXP3 interaction partners and targets. In summary, we provide a comprehensive and easily accessible resource of gene expression and gene regulation in human Treg and Tconv subpopulations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites
  • CD4-Positive T-Lymphocytes / cytology
  • Databases, Factual
  • Enhancer Elements, Genetic*
  • Epigenesis, Genetic
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genes, Reporter
  • Histones / metabolism
  • Humans
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Jurkat Cells
  • Lysine / metabolism
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic*
  • Protein Binding
  • RNA / metabolism
  • Sequence Analysis, DNA
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocytes, Regulatory / metabolism
  • Transcription Factors / metabolism
  • Transfection

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Histones
  • Interleukin-2 Receptor alpha Subunit
  • Transcription Factors
  • RNA
  • Lysine