Analysis of Interleukin-21-Induced Prdm1 Gene Regulation Reveals Functional Cooperation of STAT3 and IRF4 Transcription Factors

Hyokjoon Kwon, Danielle Thierry-Mieg, Jean Thierry-Mieg, Hyoung Pyo Kim, Jangsuk Oh, Chainarong Tunyaplin, Sebastian Carotta, Colleen E. Donovan, Matthew L. Goldman, Prafullakumar Tailor, Keiko Ozato, David E. Levy, Stephen L. Nutt, Kathryn Calame, Warren J. Leonard

Research output: Contribution to journalArticle

223 Scopus citations

Abstract

Interleukin-21 (IL-21) is a pleiotropic cytokine that induces expression of transcription factor BLIMP1 (encoded by Prdm1), which regulates plasma cell differentiation and T cell homeostasis. We identified an IL-21 response element downstream of Prdm1 that binds the transcription factors STAT3 and IRF4, which are required for optimal Prdm1 expression. Genome-wide ChIP-Seq mapping of STAT3- and IRF4-binding sites showed that most regions with IL-21-induced STAT3 binding also bound IRF4 in vivo and furthermore revealed that the noncanonical TTCnnnTAA GAS motif critical in Prdm1 was broadly used for STAT3 binding. Comparing genome-wide expression array data to binding sites revealed that most IL-21-regulated genes were associated with combined STAT3-IRF4 sites rather than pure STAT3 sites. Correspondingly, ChIP-Seq analysis of Irf4-/- T cells showed greatly diminished STAT3 binding after IL-21 treatment, and Irf4-/- mice showed impaired IL-21-induced Tfh cell differentiation in vivo. These results reveal broad cooperative gene regulation by STAT3 and IRF4.

Original languageEnglish (US)
Pages (from-to)941-952
Number of pages12
JournalImmunity
Volume31
Issue number6
DOIs
Publication statusPublished - Dec 18 2009

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Keywords

  • CELLIMMUNO
  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Kwon, H., Thierry-Mieg, D., Thierry-Mieg, J., Kim, H. P., Oh, J., Tunyaplin, C., ... Leonard, W. J. (2009). Analysis of Interleukin-21-Induced Prdm1 Gene Regulation Reveals Functional Cooperation of STAT3 and IRF4 Transcription Factors. Immunity, 31(6), 941-952. https://doi.org/10.1016/j.immuni.2009.10.008