Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors.
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.
Kwon
Hyokjoon
H
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
Thierry-Mieg
Danielle
D
Thierry-Mieg
Jean
J
Kim
Hyoung-Pyo
HP
Oh
Jangsuk
J
Tunyaplin
Chainarong
C
Carotta
Sebastian
S
Donovan
Colleen E
CE
Goldman
Matthew L
ML
Tailor
Prafullakumar
P
Ozato
Keiko
K
Levy
David E
DE
Nutt
Stephen L
SL
Calame
Kathryn
K
Leonard
Warren J
WJ
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
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