Genomic and computational approaches to dissect the mechanisms of STAT3’s universal and cell type-specific functions
Open accessAbstract
STAT3 is the quintessential pleiotropic transcription factor with many biological roles throughout development as well as in multiple adult tissues. Its functional heterogeneity is encoded in the range of genome-wide binding patterns that specify different regulatory networks in distinct cell types. However, STAT3 does not display remarkable DNA binding preferences that may help correlate specific motifs with individual biological functions or cell types. Therefore, achieving a detailed understanding of the regulatory mechanisms that endow STAT3 (or any other pleiotropic transcription factor) with such a rainbow of functions is not only a central problem in biology but also a fiendishly difficult one. Here we describe key genomic and computational approaches that have shed light into this question, and present the two current models of STAT3 binding (universal and cell type-specific). We also discuss the role that the local epigenetic environment plays in the selection of STAT3 binding sites.
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STAT3 can engage different gene expression programs in a cell-dependent and stimulating condition-dependent manner.
“several studies have reported that STAT3 can engage different gene expression programs in a cell-dependent and stimulating condition-dependent manner (Hutchins et al., 2013)”
From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Hutchins et al., 2013
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Gu, F., Dubé, N., Kim, J. W., Cheng, A., Ibarra-Sánchez, M. D. J., Tremblay, M. L., & Boisclair, Y. R. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.11.3753-3762.2003 · Cited by 136 · see citing works
Hutchins, A. P., Poulain, S., & Miranda‐Saavedra, D. (2012) · Blood · doi:10.1182/blood-2011-09-381483 · Cited by 134 · see citing works
Self-citationYoshida, Y., Kumar, A., Koyama, Y., Peng, H., Arman, A., Boch, J. A., & Auron, P. E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311498200 · Cited by 133 · see citing works
Ray, S., Boldogh, I. R., & Brasier, A. R. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.07.055 · Cited by 129 · see citing works
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Fernández, M., & Miranda‐Saavedra, D. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks149 · Cited by 121 · see citing works
Self-citationWan, E. C. K., Oh, J., Li, P., West, E. E., Wong, E., Andraski, A. B., Spolski, R. J., Yu, Z., He, J., Kelsall, B. L., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.02.011 · Cited by 117 · see citing works
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“37,38 Opposing effects of STAT3 have also been described within the same cell type: in DCs, the IL-6-mediated pro-inflammatory activity of STAT3 appears to be rapidly induced, followed by a decline, whereas the IL-10-mediated Figure 1.”
BackgroundThe Sin3a repressor complex is a master regulator of STAT transcriptional activity
Icardi, L., Mori, R., Gesellchen, V., Eyckerman, S., Cauwer, L. D., Verhelst, J., Vercauteren, K., Saelens, X., Meuleman, P., Leroux-Roels, G., et al. (2012) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1206458109 · Cited by 96 · see citing works
STAT3-Stathmin Interactions Control Microtubule Dynamics in Migrating T-cells
Verma, N. K., Dourlat, J., Davies, A. M., Long, A., Liu, W., Garbay, C., Kelleher, D. P., & Volkov, Y. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m807761200 · Cited by 96 · see citing works
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Ray, S., Lee, C., Hou, T., Boldogh, I. R., & Brasier, A. R. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn419 · Cited by 90 · see citing works
Cernkovich, E. R., Deng, J., Bond, M. C., Combs, T. P., & Harp, J. B. (2008) · Endocrinology · doi:10.1210/en.2007-1148 · Cited by 87 · see citing works
The emergence of protein complexes: quaternary structure, dynamics and allostery
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Discovery and characterization of new transcripts from RNA-seq data in mouse CD4+ T cells
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Self-citationDesigning an Enhancer Landscape
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Flagged first, then by citations
Cited by
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Epigenetic modulators, modifiers and mediators in cancer aetiology and progression
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The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges
Hutchins, A. P., Díez, D., & Miranda‐Saavedra, D. (2013) · Briefings in Functional Genomics · doi:10.1093/bfgp/elt028 · Cited by 419 · see citing works
Self-citationSTAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications
Tošić, I., & Frank, D. A. (2021) · Neoplasia · doi:10.1016/j.neo.2021.10.003 · Cited by 130 · see citing works
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STAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy
Spitzner, M., Ebner, R., Wolff, H. A., Ghadimi, Β. M., Wienands, J., & Grade, M. (2014) · Cancers · doi:10.3390/cancers6041986 · Cited by 91 · see citing works
The principles that govern transcription factor network functions in stem cells
Niwa, H. (2018) · Development · doi:10.1242/dev.157420 · Cited by 74 · see citing works
Hutchins, A. P., Takahashi, Y., & Miranda‐Saavedra, D. (2015) · Scientific Reports · doi:10.1038/srep09100 · Cited by 64 · see citing works
Self-citationGenoula, M., Franco, J. L. M., Dupont, M., Kviatcovsky, D., Milillo, M. A., Schierloh, P., Moraña, E. J., Poggi, S., Palmero, D., Mata‐Espinosa, D., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00459 · Cited by 60 · see citing works
Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells
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The Dynamic Interface of Viruses with STATs
Harrison, A. R., & Moseley, G. (2020) · Journal of Virology · doi:10.1128/jvi.00856-20 · Cited by 39 · see citing works
STAT3 as a possible therapeutic target in human malignancies: lessons from acute myeloid leukemia
Bruserud, Ø., Nepstad, I., Hauge, M., Hatfield, K. J., & Reikvam, H. (2014) · Expert Review of Hematology · doi:10.1586/17474086.2015.971005 · Cited by 39 · see citing works
Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes
Mao, X., Cho, M. J. T., Ellebrecht, C. T., Mukherjee, E. M., & Payne, A. S. (2017) · JCI Insight · doi:10.1172/jci.insight.92253 · Cited by 30 · see citing works
Díez, D., Hutchins, A. P., & Miranda‐Saavedra, D. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt913 · Cited by 29 · see citing works
Self-citationEmerging therapeutic targets for cardiac hypertrophy
Winkle, A. J., Nassal, D. M., Shaheen, R., Thomas, E., Mohta, S., Gratz, D. H., Weinberg, S. H., & Hund, T. J. (2022) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2022.2031974 · Cited by 27 · see citing works
Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux
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Azithromycin Affords Neuroprotection in Rat Undergone Transient Focal Cerebral Ischemia
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Differential effects of STAT proteins on growth hormone-mediated IGF-I gene expression
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Genomic and molecular control of cell type and cell type conversions
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Self-citationCDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci
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Geng, C., Zhang, M.-C., Manyam, G. C., Vykoukal, J. V., Fahrmann, J. F., Peng, S., Wu, C., Park, S., Kondraganti, S., Wang, D., et al. (2023) · doi:10.1158/1078-0432.24473682.v1
- Authors
- Hutchins, A. P., Diez, D., & Miranda-Saavedra, D.
- Affiliations
- Immunology Frontier Research Center, The University of Osaka (JP)
- Venue
- JAK-STAT
- Publisher
- Informa UK Limited
- Published
- 2013-10-16
- Volume
- 2
- Issue
- 4
- Pages
- e25097
- ISSN
- 2162-3988 (ISSN-L)
- 2162-3996
- PMC
- PMC3876425
- OpenAlex
- W2079761398
- Cited by
- 31
- References
- 108
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 2
- FWCI
- 0.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAK-STAT (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- STAT3, cell type-specific gene regulation, transcription factor binding sites, DNA-binding motifs, epigenetic regulation, transcriptional regulatory networks, JAK/STAT signaling
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