Epigenetic landscapes reveal transcription factors that regulate CD8 + T cell differentiation

Nat Immunol. 2017 May;18(5):573-582. doi: 10.1038/ni.3706. Epub 2017 Mar 13.

Abstract

Dynamic changes in the expression of transcription factors (TFs) can influence the specification of distinct CD8+ T cell fates, but the observation of equivalent expression of TFs among differentially fated precursor cells suggests additional underlying mechanisms. Here we profiled the genome-wide histone modifications, open chromatin and gene expression of naive, terminal-effector, memory-precursor and memory CD8+ T cell populations induced during the in vivo response to bacterial infection. Integration of these data suggested that the expression and binding of TFs contributed to the establishment of subset-specific enhancers during differentiation. We developed a new bioinformatics method using the PageRank algorithm to reveal key TFs that influence the generation of effector and memory populations. The TFs YY1 and Nr3c1, both constitutively expressed during CD8+ T cell differentiation, regulated the formation of terminal-effector cell fates and memory-precursor cell fates, respectively. Our data define the epigenetic landscape of differentiation intermediates and facilitate the identification of TFs with previously unappreciated roles in CD8+ T cell differentiation.

Publication types

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

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / microbiology
  • CD8-Positive T-Lymphocytes / physiology*
  • Cell Differentiation / genetics
  • Computational Biology
  • Enhancer Elements, Genetic / genetics
  • Epigenesis, Genetic*
  • Gene Expression Profiling
  • Histones / metabolism
  • Immunologic Memory / genetics
  • Listeriosis / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • T-Lymphocyte Subsets / microbiology
  • T-Lymphocyte Subsets / physiology*
  • YY1 Transcription Factor / genetics
  • YY1 Transcription Factor / metabolism*

Substances

  • Histones
  • NR3C1 protein, mouse
  • Receptors, Glucocorticoid
  • YY1 Transcription Factor
  • Yy1 protein, mouse