A Genomic Regulatory Element That Directs Assembly and Function of Immune-Specific AP-1–IRF Complexes
Open accessAbstract
Helping T Helper Transcription: Members of the interferon response family of transcription factors (IRFs) are specifically expressed in immune cells and are known to regulate their differentiation. IRF4 and IRF8 regulate gene expression by binding to other transcription factors, which results in their recruitment to composite motifs in the genome. Although the specific mechanism of how this regulation works in some immune cells is understood, how it occurs in T cells is not clear because the transcription factors that normally partner with IRFs are absent. Using genomic analysis, Glasmacher et al. (p. 975 , published online 13 September; see the Perspective by Martinez and Rao ) now identify IRF4–AP-1 composite elements in T helper 17 (T H 17) cells and show that IRF4 and the AP-1 factor Batf cooperatively assemble on a large array of genes required for T H 17 cell differentiation and function. Assembly of such heterodimers was also observed in T H 2 cells, B cells, and dendritic cells, which suggests the general importance of this motif in immune cell differentiation.
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Genes affected by positive or negative regulators significantly overlap with genes bound by key CD4+ transcription factors Foxp3, Batf, Irf4, and ROR-γt.
“The genes affected by either positive or negative regulators also significantly overlap with those bound by key CD4+ transcription factors (e.g., Foxp326,27, Batf, Irf4, and ROR-γt28,29, Xiao et al., unpublished data).”
From Dynamic regulatory network controlling TH17 cell differentiation (2013) · cites this paper as [28]
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UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 45,260 · see citing works
Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., & Littman, D. R. (2006) · Cell · doi:10.1016/j.cell.2006.07.035 · Cited by 5,145 · see citing works
Self-citationFitting a mixture model by expectation maximization to discover motifs in biopolymers.
Bailey, T. L., & Elkan, C. (1994) · PubMed · Cited by 4,933 · see citing works
FIMO: scanning for occurrences of a given motif
Grant, C. E., Bailey, T. L., & Noble, W. S. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr064 · Cited by 4,247 · see citing works
Genome-Wide Mapping of in Vivo Protein-DNA Interactions
Johnson, D. S., Mortazavi, A., Myers, R. M., & Wold, B. (2007) · Science · doi:10.1126/science.1141319 · Cited by 2,927 · see citing works
Lu, X. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg680 · Cited by 1,669 · see citing works
T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors RORα and RORγ
Yang, X. O., Pappu, B. P., Nurieva, R., Akimzhanov, A., Kang, H. S., Chung, Y., Ma, L., Shah, B., Panopoulos, A. D., Schluns, K. S., et al. (2008) · Immunity · doi:10.1016/j.immuni.2007.11.016 · Cited by 1,605 · see citing works
Self-citationSTAT3 Regulates Cytokine-mediated Generation of Inflammatory Helper T Cells
Yang, X. O., Panopoulos, A. D., Nurieva, R., Chang, S. H., Wang, D., Watowich, S. S., & Dong, C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.c600321200 · Cited by 1,494 · see citing works
Self-citationAP-1 subunits: quarrel and harmony among siblings
Heß, J., Angel, P. E., & Schorpp‐Kistner, M. (2004) · Journal of Cell Science · doi:10.1242/jcs.01589 · Cited by 1,305 · see citing works
A Critical Role for Dnmt1 and DNA Methylation in T Cell Development, Function, and Survival
Lee, P. P., Fitzpatrick, D. R., Beard, C., Jessup, H. K., Lehar, S. M., Makar, K. W., Pérez‐Melgosa, M., Sweetser, M. T., Schlissel, M. S., Nguyen, S. P., et al. (2001) · Immunity · doi:10.1016/s1074-7613(01)00227-8 · Cited by 1,280 · see citing works
The IRF Family Transcription Factors in Immunity and Oncogenesis
Tamura, T., Yanai, H., Savitsky, D., & Taniguchi, T. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090400 · Cited by 1,259 · see citing works
Current Protocols in Bioinformatics
Korch, C. T. (2002) · John Wiley & Sons, Inc. eBooks · doi:10.1002/0471250953 · Cited by 1,226 · see citing works
Th17 and regulatory T cells in mediating and restraining inflammation
Littman, D. R., & Rudensky, A. Y. (2010) · Cell · doi:10.1016/j.cell.2010.02.021 · Cited by 1,039 · see citing works
Self-citationRegulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses
Zheng, Y., Chaudhry, A., Kas, A., deRoos, P., Kim, J. M., Chu, T.-T., Corcoran, L., Treuting, P., Klein, U., & Rudensky, A. Y. (2009) · Nature · doi:10.1038/nature07674 · Cited by 958 · see citing works
Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination
Klein, U., Casola, S. S., Cattoretti, G., Shen, Q. “., Lia, M., Mo, T., Ludwig, T. E., Rajewsky, K., & Dalla‐Favera, R. (2006) · Nature Immunology · doi:10.1038/ni1357 · Cited by 802 · see citing works
Genome-wide analysis of transcription factor binding sites based on ChIP-Seq data
Valouev, A., Johnson, D. S., Sundquist, A., Medina, C., Anton, E., Batzoglou, S., Myers, R. M., & Sidow, A. (2008) · Nature Methods · doi:10.1038/nmeth.1246 · Cited by 695 · see citing works
The development of inflammatory TH-17 cells requires interferon-regulatory factor 4
Brüstle, A., Heink, S., Huber, M., Rosenplänter, C., Stadelmann, C., Yu, P., Arpaia, E., Mak, T. W., Kamradt, T., & Lohoff, M. D. (2007) · Nature Immunology · doi:10.1038/ni1500 · Cited by 691 · see citing works
The AP-1 transcription factor Batf controls TH17 differentiation
Schraml, B. U., Hildner, K., Ise, W., Lee, W.-L., Smith, W. A.-E., Solomon, B. D., Sahota, G., Sim, J. E., Mukasa, R., Čemerski, S., et al. (2009) · Nature · doi:10.1038/nature08114 · Cited by 622 · see citing works
Self-citationSciammas, R., Shaffer, A. L., Schatz, J. H., Zhao, H., Staudt, L. M., & Singh, H. (2006) · Immunity · doi:10.1016/j.immuni.2006.07.009 · Cited by 564 · see citing works
Self-citationStat3 and Stat4 Direct Development of IL-17-Secreting Th Cells
Mathur, A. N., Chang, H., Zisoulis, D. G., Stritesky, G. L., Yu, Q., O’Malley, J. T., Kapur, R., Levy, D. E., Kansas, G. S., & Kaplan, M. H. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.8.4901 · Cited by 548 · see citing works
Kimura, A., Naka, T., Nohara, K., Fujii‐Kuriyama, Y., & Kishimoto, T. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804231105 · Cited by 540 · see citing works
Use of Non-crystallographic Symmetry in Protein Structure Refinement
Kleywegt, G. J. (1996) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444995016477 · Cited by 486 · see citing works
Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator.
Eisenbeis, C. F., Singh, H., & Storb, U. (1995) · Genes & Development · doi:10.1101/gad.9.11.1377 · Cited by 447 · see citing works
Self-citationTamura, T., Tailor, P. B., Yamaoka, K., Kong, H. J., Tsujimura, H., O’Shea, J. J., Singh, H., & Ozato, K. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.5.2573 · Cited by 422 · see citing works
Self-citationCompensatory dendritic cell development mediated by BATF–IRF interactions
Tussiwand, R., Lee, W.-L., Murphy, T. L., Mashayekhi, M., Wumesh, K. C., Albring, J. C., Satpathy, A. T., Rotondo, J. A., Edelson, B. T., Kretzer, N. M., et al. (2012) · Nature · doi:10.1038/nature11531 · Cited by 419 · see citing works
Self-citationIse, W., Kohyama, M., Schraml, B. U., Zhang, T., Schwer, B., Basu, U., Alt, F. W., Tang, J., Oltz, E. M., Murphy, T. L., et al. (2011) · Nature Immunology · doi:10.1038/ni.2037 · Cited by 377 · see citing works
Self-citationKwon, H., Thierry‐Mieg, D., Thierry‐Mieg, J., Kim, H., Oh, J., Tunyaplin, C., Carotta, S., Donovan, C. E., Goldman, M. L., Tailor, P. B., et al. (2009) · Immunity · doi:10.1016/j.immuni.2009.10.008 · Cited by 357 · see citing works
Rengarajan, J., Mowen, K. A., McBride, K. D., Smith, E. D., Singh, H., & Glimcher, L. H. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20011128 · Cited by 332 · see citing works
Self-citationMacián, F., García‐Rodríguez, C., & Rao, A. (2000) · The EMBO Journal · doi:10.1093/emboj/19.17.4783 · Cited by 329 · see citing works
Huber, M., Brüstle, A., Reinhard, K., Guralnik, A., Walter, G. J., Mahiny, A. J., von Löw, E., & Lohoff, M. D. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809077106 · Cited by 280 · see citing works
Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4
Lohoff, M. D., Mittrücker, H., Prechtl, S., Bischof, S., Sommer, F. O., Kock, S., Ferrick, D. A., Duncan, G. S., Gessner, A., & Mak, T. W. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182425099 · Cited by 253 · see citing works
Brass, A. L., Kehrli, E., Eisenbeis, C. F., Storb, U., & Singh, H. (1996) · Genes & Development · doi:10.1101/gad.10.18.2335 · Cited by 242 · see citing works
Self-citationMatsuyama, T., Grossman, A., Mittrücker, H.-W., Siderovski, D. P., Kiefer, F., Kawakami, T., Richardson, C. D., Taniguchi, T., Yoshinaga, S. K., & Mak, T. W. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.12.2127 · Cited by 232 · see citing works
Peters, A., Lee, Y., & Kuchroo, V. K. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.08.007 · Cited by 232 · see citing works
Computational representation of developmental genetic regulatory networks
Longabaugh, W. J. R., Davidson, E. H., & Bolouri, H. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.04.023 · Cited by 215 · see citing works
Roles of interferon-regulatory factors in T-helper-cell differentiation
Lohoff, M. D., & Mak, T. W. (2005) · Nature reviews. Immunology · doi:10.1038/nri1552 · Cited by 214 · see citing works
Brass, A. L., Zhu, A. Q., & Singh, H. (1999) · The EMBO Journal · doi:10.1093/emboj/18.4.977 · Cited by 207 · see citing works
Self-citationRegulation and Function of Proinflammatory TH17 Cells
Martínez, G., Nurieva, R., Yang, X. O., & Dong, C. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1443.021 · Cited by 203 · see citing works
Self-citationBollig, N., Brüstle, A., Kellner, K., Ackermann, W., Abass, E. M., Raifer, H., Camara, B., Brendel, C. A., Giel, G., Bothur, E., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1205834109 · Cited by 200 · see citing works
Self-citationCrystal structure of ATF‐2/c‐Jun and IRF‐3 bound to the interferon‐β enhancer
Panne, D., Maniatis, T., & Harrison, S. (2004) · EMBO Journal · doi:10.1038/sj.emboj.7600453 · Cited by 182 · see citing works
Bovolenta, C., Driggers, P. H., Marks, M. S., Medin, J. A., Politis, A. D., Vogel, S. N., Levy, D. E., Sakaguchi, K., Appella, E., & Coligan, J. E. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.11.5046 · Cited by 167 · see citing works
Crystal structure of PU. 1/IRF-4/DNA ternary complex
Escalante, C. R., Brass, A. L., Pongubala, J. M. R., Shatova, E., Shen, L., Singh, H., & Aggarwal, A. K. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00703-7 · Cited by 154 · see citing works
Self-citationThe diverse roles of IRF4 in late germinal center B‐cell differentiation
Silva, N. S. D., Simonetti, G., Heise, N., & Klein, U. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01113.x · Cited by 141 · see citing works
Transcription of Il17 and Il17f Is Controlled by Conserved Noncoding Sequence 2
Wang, X., Zhang, Y.-B., Yang, X. O., Nurieva, R., Chang, S. H., Ojeda, S. S., Kang, H. S., Schluns, K. S., Gui, J., Jetten, A. M., et al. (2012) · Immunity · doi:10.1016/j.immuni.2011.10.019 · Cited by 125 · see citing works
Self-citationTranscription factor IRF8 directs a silencing programme for TH17 cell differentiation
Ouyang, X., Zhang, R., Yang, J., Li, Q., Qin, L., Zhu, C. Y., Liu, J., Ning, H., Shin, M. S., Gupta, M., et al. (2011) · Nature Communications · doi:10.1038/ncomms1311 · Cited by 119 · see citing works
IRF4 regulates IL-17A promoter activity and controls RORγt-dependent Th17 colitis in vivo
Mudter, J., Yu, J., Zufferey, C., Brüstle, A., Wirtz, S. J., Weigmann, B., Hoffman, A. W., Schenk, M., Galle, P. R., Lehr, H. A., et al. (2011) · Inflammatory Bowel Diseases · doi:10.1002/ibd.21476 · Cited by 108 · see citing works
Lee, C., Kang, K., So, J., Kwon, H., Son, J.-S., Song, M., Sahoo, A., Yi, H.-J., Hwang, K.-C., Matsuyama, T., et al. (2008) · Molecular Immunology · doi:10.1016/j.molimm.2008.07.037 · Cited by 84 · see citing works
INTERNATIONAL CONFERENCE ON INTELLIGENT SYSTEMS FOR MOLECULAR BIOLOGY (ISMB)
Goldberg, D. S., Hibbs, M., Käll, L., et al. (2009) · University of North Texas Digital Library (University of North Texas) · Cited by 32 · see citing works
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- Authors
- Glasmacher, E., Agrawal, S., Chang, A. B., Murphy, T. L., Zeng, W., Vander Lugt, B., Khan, A. A., Ciofani, M., Spooner, C. J., Rutz, S., Hackney, J., Nurieva, R., Escalante, C. R., Ouyang, W., Littman, D. R., Murphy, K. M., & Singh, H.
- Affiliations
- Genentech (US)
- Howard Hughes Medical Institute (US)
- Department of Discovery Immunology, Genentech, Incorporated, South San Francisco, CA 94080, USA.
- University of Chicago (US)
- The University of Texas MD Anderson Cancer Center (US)
- Virginia Commonwealth University (US)
- Corresponding author
- Glasmacher, Elke
- Agrawal, Smita
- Chang, Abraham B.
- Murphy, Theresa L.
- Zeng, Wenwen
- Murphy, Kenneth M.
- Singh, Harinder
- ORCID
- Venue
- Science
- Published
- 2012-11-16
- Volume
- 338
- Issue
- 6109
- Pages
- 975-980
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5789805
- OpenAlex
- W2065391646
- Cited by
- 361
- References
- 48
- Citations by year
- 2026: 24 · 2025: 25 · 2024: 22 · 2023: 20 · 2022: 19 · 2021: 24 · 2020: 25 · 2019: 28 · 2018: 17 · 2017: 28 · 2016: 26 · 2015: 28 · 2014: 29 · 2013: 44 · 2012: 2
- FWCI
- 13.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1rc4ai092765-01, 1rc1ai087266-01)
- Genentech
- National Institute of Allergy and Infectious Diseases (RC1-AI087266, RC4-AI092765)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- IRF4, IRF8, BATF, Th17 cells, Th2 cells, dendritic cell differentiation, B cell differentiation, macrophage differentiation, transcriptional regulation, gene activation, ChIP-seq
- MeSH terms
- Interferon Regulatory Factor-8, Interferon Regulatory Factor-4, Animals, Cell Differentiation, Humans, Mice, Inbred C57BL, Transcriptional Activation, Transcription Factor AP-1, Chromatin Immunoprecipitation, Regulatory Elements, Transcriptional, Interferon Regulatory Factors, Basic-Leucine Zipper Transcription Factors, Mice, Immunomodulation, Th17 Cells
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