Asymmetric Action of STAT Transcription Factors Drives Transcriptional Outputs and Cytokine Specificity

Immunity. 2015 May 19;42(5):877-89. doi: 10.1016/j.immuni.2015.04.014.

Abstract

Interleukin-6 (IL-6) and IL-27 signal through a shared receptor subunit and employ the same downstream STAT transcription proteins, but yet are ascribed unique and overlapping functions. To evaluate the specificity and redundancy for these cytokines, we quantified their global transcriptomic changes and determined the relative contributions of STAT1 and STAT3 using genetic models and chromatin immunoprecipitation-sequencing (ChIP-seq) approaches. We found an extensive overlap of the transcriptomes induced by IL-6 and IL-27 and few examples in which the cytokines acted in opposition. Using STAT-deficient cells and T cells from patients with gain-of-function STAT1 mutations, we demonstrated that STAT3 is responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 is the principal driver of specificity. STAT1 cannot compensate in the absence of STAT3 and, in fact, much of STAT1 binding to chromatin is STAT3 dependent. Thus, STAT1 shapes the specific cytokine signature superimposed upon STAT3's action.

Publication types

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

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Chromatin / chemistry
  • Chromatin / metabolism*
  • Cytokines / metabolism*
  • Gene Expression Regulation / immunology*
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Inbred C57BL
  • Models, Immunological*
  • Mutation
  • STAT Transcription Factors / metabolism*
  • STAT1 Transcription Factor / chemistry
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • Transcriptome

Substances

  • Chromatin
  • Cytokines
  • STAT Transcription Factors
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor

Associated data

  • GEO/GSE65621