T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements
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T-bet and GATA3 regulate the CD4+ T cell Th1/Th2 cell fate decision but little is known about the interplay between these factors outside of the murine Ifng and Il4/Il5/Il13 loci. Here we show that T-bet and GATA3 bind to multiple distal sites at immune regulatory genes in human effector T cells. These sites display markers of functional elements, act as enhancers in reporter assays and are associated with a requirement for T-bet and GATA3. Furthermore, we demonstrate that both factors bind distal sites at Tbx21 and that T-bet directly activates its own expression. We also show that in Th1 cells, GATA3 is distributed away from Th2 genes, instead occupying T-bet binding sites at Th1 genes, and that T-bet is sufficient to induce GATA3 binding at these sites. We propose these aspects of T-bet and GATA3 function are important for Th1/Th2 differentiation and for understanding transcription factor interactions in other T cell lineage decisions. T-bet and GATA3 regulate differentiation of T cells into Th1 or Th2 cell fates, but little is known about their functional interaction outside of the IFNγ and Il4 /Il5/Il13 loci. Kanhere et al. map these factors across the genome in human T cells, revealing unappreciated breadth of function and interplay between them.
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The theft mechanism of repression by partner factor redistribution is not unique to the PU.1-Runx1 pair.
“The “theft” mechanism of repression by partner factor redistribution is not unique to the PU.1-Runx1 pair.”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [117]
A very similar phenomenon has been reported earlier for the effect of T-bet on GATA-3 in establishing the Th1 cell program.
“A very similar phenomenon has been reported earlier by Jenner and colleagues for the effect of T-bet on GATA-3 in establishing the Th1 cell program (117, 118).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [117]
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“A very similar phenomenon has been reported earlier by Jenner and colleagues for the effect of T-bet on GATA3 in establishing the Th1 cell program (117, 118).”
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- Authors
- Kanhere, A., Hertweck, A., Bhatia, U., Gökmen, M. R., Perucha, E., Jackson, I., Lord, G. M., & Jenner, R. G.
- Affiliations
- University College London (GB)
- Guy's Hospital (GB)
- Corresponding author
- Lord, Graham M.
- Jenner, Richard G.
- ORCID
- Venue
- Nature Communications
- Published
- 2012-12-11
- Volume
- 3
- Issue
- 1
- Pages
- 1268-1268
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3535338
- OpenAlex
- W2015280752
- Cited by
- 345
- References
- 52
- Citations by year
- 2026: 11 · 2025: 32 · 2024: 18 · 2023: 22 · 2022: 32 · 2021: 35 · 2020: 33 · 2019: 24 · 2018: 33 · 2017: 27 · 2016: 20 · 2015: 18 · 2014: 22 · 2013: 18
- FWCI
- 8.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust (091009)
- King's College Hospital NHS Foundation Trust
- National Institute for Health and Care Research (CL-2010-17-010)
- King's College London
- Medical Research Council (G0802068, MR/J006742/1, G0900950)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- T-bet, GATA3, Th1/Th2 differentiation, CD4+ T cells, distal regulatory elements, enhancers, TBX21, transcription factor binding sites, transcriptional regulation
- MeSH terms
- T-bet Transcription Factor, Animals, Binding Sites, Cell Differentiation, Humans, Mice, Inbred BALB C, Regulatory Sequences, Nucleic Acid, CD4-Positive T-Lymphocytes, Th1 Cells, Th2 Cells, Gene Expression Regulation, Developmental, Oligonucleotide Array Sequence Analysis, T-Box Domain Proteins, GATA3 Transcription Factor, Mice
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