title: Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors.
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.
authors.affiliation: Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Hyokjoon
authors.initials: H
authors.lastname: Kwon
authors.forename: Danielle
authors.initials: D
authors.lastname: Thierry-Mieg
authors.forename: Jean
authors.initials: J
authors.lastname: Thierry-Mieg
authors.forename: Hyoung-Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Jangsuk
authors.initials: J
authors.lastname: Oh
authors.forename: Chainarong
authors.initials: C
authors.lastname: Tunyaplin
authors.forename: Sebastian
authors.initials: S
authors.lastname: Carotta
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Donovan
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Goldman
authors.forename: Prafullakumar
authors.initials: P
authors.lastname: Tailor
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.forename: Kathryn
authors.initials: K
authors.lastname: Calame
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D007438:Introns; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D000074462:Positive Regulatory Domain I-Binding Factor 1; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D007378:Interleukins; D000074462:Positive Regulatory Domain I-Binding Factor 1; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4; C513258:Prdm1 protein, mouse