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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 
 IMMUNITY, Vol.31(6) : 941-952, 2009 
Journal Title
Issue Date
Animals ; B-Lymphocytes/immunology ; Base Sequence ; Binding Sites ; CD4-Positive T-Lymphocytes/immunology ; Cell Differentiation ; Gene Expression Regulation* ; Genome-Wide Association Study ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism* ; Interleukins/metabolism* ; Introns ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Sequence Data ; Positive Regulatory Domain I-Binding Factor 1 ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism* ; Transcription Factors/genetics*
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.
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1. College of Medicine (의과대학) > Dept. of Environmental Medical Biology (환경의생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyoung Pyo(김형표) ORCID logo https://orcid.org/0000-0003-1441-8822
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