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BATF–JUN is critical for IRF4-mediated transcription in T cells

Nature volume 490, pages 543–546 (2012)Cite this article

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Abstract

Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response1,2. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity3, allowing IRF4 to regulate genes containing ETS–IRF composite elements (EICEs; 5′-GGAAnnGAAA-3′)1. Here we show that in mouse CD4+ T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1–IRF4 composite (5′-TGAnTCA/GAAA-3′) motifs that we denote as AP1–IRF composite elements (AICEs). Moreover, BATF–JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4+ T cells stimulated with IL-21 and in TH17 differentiated cells. Importantly, BATF binding was diminished in Irf4−/− T cells and IRF4 binding was diminished in Batf−/− T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in TH17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription.

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Figure 1: Preferential IRF4 binding to AP1 motifs in T cells.
Figure 2: Functionally important IRF4 binding to AP1 sites.
Figure 3: Cooperative IRF4/BATF/JUN binding.
Figure 4: Cooperative action of IRF4, BATF, and JUN.

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Gene Expression Omnibus

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Acknowledgements

This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH (P.L., R.S., W.L., L.W. and W.J.L.) and the Howard Hughes Medical Institute (T.L.M. and K.M.M.). We thank J.-X. Lin for valuable suggestions, critical comments and RNA-Seq data for pro-B/pre-B-enriched populations. We thank J. Zhu and Y. Wakabayashi, NHLBI DNA Sequencing Core, for excellent services, K. Ozato and Y. Hiroaki, NICHD, for Irf4−/− mice, and J. Thierry-Mieg and D. Thierry-Mieg, NCBI, for early analysis of ChIP-Seq data from ref. 14.

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Author notes

  1. Peng Li and Rosanne Spolski: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, 20892-1674, Maryland, USA

    Peng Li, Rosanne Spolski, Wei Liao, Lu Wang & Warren J. Leonard

  2. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Theresa L. Murphy & Kenneth M. Murphy

  3. Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Kenneth M. Murphy

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Contributions

P.L. designed experiments, analysed data and wrote the paper. R.S. designed and performed experiments, analysed data and wrote the paper. W.L. and L.W. designed and performed experiments and analysed data. T.L.M. and K.M.M. provided reagents and made suggestions. W.J.L. designed experiments, analysed data and wrote the paper.

Corresponding authors

Correspondence to Peng Li or Warren J. Leonard.

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Competing interests

W.J.L. and R.S. are inventors on NIH patents related to IL-21.

Additional information

Data sets (ChIP-Seq and RNA-Seq data) have been deposited in the Gene Expression Omnibus (GSE39756).

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Supplementary Information

This file contains Supplementary Figures 1-8 and Supplementary Tables 1-2. (PDF 1876 kb)

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Li, P., Spolski, R., Liao, W. et al. BATF–JUN is critical for IRF4-mediated transcription in T cells. Nature 490, 543–546 (2012). https://doi.org/10.1038/nature11530

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