Global Mapping of H3K4me3 and H3K27me3 Reveals Specificity and Plasticity in Lineage Fate Determination of Differentiating CD4+ T Cells
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Multipotential naive CD4(+) T cells differentiate into distinct lineages including T helper 1 (Th1), Th2, Th17, and inducible T regulatory (iTreg) cells. The remarkable diversity of CD4(+) T cells begs the question whether the observed changes reflect terminal differentiation with heritable epigenetic modifications or plasticity in T cell responses. We generated genome-wide histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) trimethylation maps in naive, Th1, Th2, Th17, iTreg, and natural Treg (nTreg) cells. We found that although modifications of signature-cytokine genes (Ifng, Il4, and Il17) partially conform to the expectation of lineage commitment, genes encoding transcription factors like Tbx21 exhibit a broad spectrum of epigenetic states, consistent with our demonstration of T-bet and interferon-gamma induction in nTreg cells. Our data suggest an epigenetic mechanism underlying the specificity and plasticity of effector and regulatory T cells and also provide a framework for understanding complexity of CD4(+) T helper cell differentiation.
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GSEA using a previously defined Th17-Th1 gene set identified significant enrichment of Th1-related genes in Il6ra−/− T cells ex vivo, while the transcriptome of WT T cells was enriched for a subset of genes related to Th17 cells ex vivo.
“Gene set enrichment analysis (GSEA) using a previously defined Th17–Th1 gene set (57) identified significant enrichment of Th1-related genes in Il6ra−/− T cells ex vivo (Fig. 6E, right and Supplementary Fig. 7). Conversely, and in accord with our previous findings, the transcriptome of WT T cells was enriched for a subset of genes related to Th17 cells ex vivo”
From T <sub>H</sub> 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity (2020) · cites this paper as [57]
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Bam, M., Yang, X., Zhou, J., Ginsberg, J. P., Leyden, Q., Nagarkatti, P. S., & Nagarkatti, M. (2016) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-015-9643-8 · Cited by 103 · see citing works
Protein phosphatase 2A enables expression of interleukin 17 (IL-17) through chromatin remodeling
Apostolidis, S. A., Rauen, T., Hedrich, C. M., Tsokos, G. C., & Crispín, J. C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.483743 · Cited by 91 · see citing works
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Signal transduction and Th17 cell differentiation
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Self-citationTh17 cell pathogenicity in autoimmune disease
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Polycomb proteins in hematologic malignancies
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Rapid Recall Ability of Memory T cells is Encoded in their Epigenome
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- Authors
- Wei, G., Wei, L., Zhu, J., Zang, C., Hu-Li, J., Yao, Z., Cui, K., Kanno, Y., Roh, T.-Y., Watford, W. T., Schones, D. E., Peng, W., Sun, H.-W., Paul, W. E., O'Shea, J. J., & Zhao, K.
- Affiliations
- National Institutes of Health (US)
- George Washington University (US)
- Corresponding author
- Zhao, Keji
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 30
- Issue
- 1
- Pages
- 155-167
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC2722509
- OpenAlex
- W2092345398
- Cited by
- 1,152
- References
- 7
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 47 · 2023: 48 · 2022: 36 · 2021: 60 · 2020: 46 · 2019: 54 · 2018: 52 · 2017: 60 · 2016: 62 · 2015: 77 · 2014: 88 · 2013: 99 · 2012: 100
- FWCI
- 53.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Open Access System for Information Sharing (Pohang University of Science and Technology) (submittedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Diseases
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- H3K4me3, H3K27me3, histone trimethylation, CD4+ T cell differentiation, Th1 cells, Th2 cells, Th17 cells, epigenetic plasticity, lineage commitment, TBX21, T-bet, interferon-gamma, cytokine gene regulation, naive T cells
- MeSH terms
- Animals, Chromosome Mapping, DNA-Binding Proteins, Histones, Mice, Inbred C57BL, Oxidoreductases, N-Demethylating, CD4-Positive T-Lymphocytes, CD4 Antigens, T-Lymphocyte Subsets, Cell Lineage, Protein Modification, Translational, Mice, Jumonji Domain-Containing Histone Demethylases, Retinoblastoma-Binding Protein 2
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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