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

doi:10.1016/j.immuni.2009.10.008

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 journal › Article › peer-review

290 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 language	English (US)
Pages (from-to)	941-952
Number of pages	12
Journal	Immunity
Volume	31
Issue number	6
DOIs	https://doi.org/10.1016/j.immuni.2009.10.008
State	Published - Dec 18 2009
Externally published	Yes

Keywords

CELLIMMUNO
MOLIMMUNO

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.immuni.2009.10.008

Cite this

Kwon, H., Thierry-Mieg, D., Thierry-Mieg, J., Kim, H. P., Oh, J., Tunyaplin, C., Carotta, S., Donovan, C. E., Goldman, M. L., Tailor, P., Ozato, K., Levy, D. E., Nutt, S. L., Calame, K., & 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

Kwon, H, Thierry-Mieg, D, Thierry-Mieg, J, Kim, HP, Oh, J, Tunyaplin, C, Carotta, S, Donovan, CE, Goldman, ML, Tailor, P, Ozato, K, Levy, DE, Nutt, SL, Calame, K & Leonard, WJ 2009, 'Analysis of Interleukin-21-Induced Prdm1 Gene Regulation Reveals Functional Cooperation of STAT3 and IRF4 Transcription Factors', Immunity, vol. 31, no. 6, pp. 941-952. https://doi.org/10.1016/j.immuni.2009.10.008

@article{30612a460af14e0a94ad13e10dc0c990,

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.",

keywords = "CELLIMMUNO, MOLIMMUNO",

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

note = "Funding Information: We thank H.C. Morse III for NFS201 and NFS202 cells, D.E. Schones for valuable discussions and assistance with handling the Illumina raw ChIP-Seq data and for processing ChIP-Seq data, K. Cui and T.-Y. Roh for help with Solexa sequencing, the NHLBI Affymetrix Core and N. Raghavachari, X. Xu, and D. Liu for help with generating, analyzing, and handling Affymetrix data, and J.-X. Lin, H. Young, K. Zhao, and K.-T. Jeang for valuable discussions and/or critical comments. This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and by the National Center for Biotechnology Information, National Library of Medicine. W.J.L. is an inventor on patents and patent applications related to IL-21. ",

year = "2009",

month = dec,

day = "18",

doi = "10.1016/j.immuni.2009.10.008",

language = "English (US)",

volume = "31",

pages = "941--952",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Analysis of Interleukin-21-Induced Prdm1 Gene Regulation Reveals Functional Cooperation of STAT3 and IRF4 Transcription Factors

AU - Kwon, Hyokjoon

AU - Thierry-Mieg, Danielle

AU - Thierry-Mieg, Jean

AU - Kim, Hyoung Pyo

AU - Oh, Jangsuk

AU - Tunyaplin, Chainarong

AU - Carotta, Sebastian

AU - Donovan, Colleen E.

AU - Goldman, Matthew L.

AU - Tailor, Prafullakumar

AU - Ozato, Keiko

AU - Levy, David E.

AU - Nutt, Stephen L.

AU - Calame, Kathryn

AU - Leonard, Warren J.

N1 - Funding Information: We thank H.C. Morse III for NFS201 and NFS202 cells, D.E. Schones for valuable discussions and assistance with handling the Illumina raw ChIP-Seq data and for processing ChIP-Seq data, K. Cui and T.-Y. Roh for help with Solexa sequencing, the NHLBI Affymetrix Core and N. Raghavachari, X. Xu, and D. Liu for help with generating, analyzing, and handling Affymetrix data, and J.-X. Lin, H. Young, K. Zhao, and K.-T. Jeang for valuable discussions and/or critical comments. This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and by the National Center for Biotechnology Information, National Library of Medicine. W.J.L. is an inventor on patents and patent applications related to IL-21.

PY - 2009/12/18

Y1 - 2009/12/18

N2 - 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.

AB - 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.

KW - CELLIMMUNO

KW - MOLIMMUNO

UR - http://www.scopus.com/inward/record.url?scp=71749089605&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=71749089605&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2009.10.008

DO - 10.1016/j.immuni.2009.10.008

M3 - Article

C2 - 20064451

AN - SCOPUS:71749089605

SN - 1074-7613

VL - 31

SP - 941

EP - 952

JO - Immunity

JF - Immunity

IS - 6

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this