Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Christian Schmidl1,
  2. Leo Hansmann1,
  3. Timo Lassmann2,
  4. Piotr J. Balwierz3,
  5. Hideya Kawaji4,
  6. Masayoshi Itoh5,
  7. Jun Kawai2,
  8. Sayaka Nagao-Sato2,
  9. Harukazu Suzuki2,
  10. Reinhard Andreesen6,
  11. Yoshihide Hayashizaki2,
  12. Alistair R. R. Forrest2,
  13. Piero Carninci2,
  14. Petra Hoffmann1,
  15. Matthias Edinger1, and
  16. Michael Rehli1,*
  1. 1 Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany;
  2. 2 RIKEN Omics Science Center, Yokohama, Kanagawa, Japan;
  3. 3 Biozentrum, University of Basel, and Swiss Institute of Bioinformatics, Basel, Switzerland;
  4. 4 RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, Japan;
  5. 5 RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama, Japan;
  6. 6 Regensburg Centre for Interventional Immunology, Regensburg, Germany
  1. * Corresponding author; email: michael.rehli{at}

Key points

  • Transcription and enhancer profiling reveal cell type-specific regulome architectures and transcription factor networks in conventional and regulatory T cells.


CD4+CD25+FOXP3+ human regulatory T cells (Tregs) are essential for self-tolerance and immune homeostasis. Here, we describe the promoterome of CD4+CD25highCD45RA+ naïve and CD4+CD25highCD45RA-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.

  • Submitted February 25, 2013.
  • Accepted July 1, 2013.