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Transcriptional and Epigenetic Control of T Helper Cell Specification: Molecular Mechanisms Underlying Commitment and Plasticity
Open accessAbstract
T helper cell differentiation occurs in the context of the extracellular cytokine milieu evoked by diverse microbes and other pathogenic stimuli along with T cell receptor stimulation. The culmination of these signals results in specification of T helper lineages, which occurs through the combinatorial action of multiple transcription factors that establish distinctive transcriptomes. In this manner, inducible, but constitutively active, master regulators work in conjunction with factors such as the signal transducer and activator of transcriptions (STATs) that sense the extracellular environment. The acquisition of a distinctive transcriptome also depends on chromatin modifications that impact key cis elements as well as the changes in global genomic organization. Thus, signal transduction and epigenetics are linked in these processes of differentiation. In this review, recent advances in understanding T helper lineage specification and deciphering the action of transcription factors are summarized with emphasis on comprehensive views of the dynamic T cell epigenome.
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“Differentiation of T cells to specific TH lineages is driven by specific transcription factors but reinforced by epigenetic modifications on histone tails (H3K4 and H3K27 trimethylation) and DNA methylation of CpG dinucleotides (103).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [103]
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BackgroundMethodInfluentialCTCF-mediated functional chromatin interactome in pluripotent cells
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Comprehensive methylome map of lineage commitment from haematopoietic progenitors
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“This method relies on the nature of bisulfite treatment to selectively convert unmethylated cytosine to uracil so that subsequent deep sequencing would distinguish differential methylation status on a given cytosine residue at a single nucleotide resolution (34, 91).”
MethodRNA meets chromatinPreprint
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9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response
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Reversal of Histone Methylation: Biochemical and Molecular Mechanisms of Histone Demethylases
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“Using genome-wide ChIP-seq analysis, it has noted that STAT3 and STAT5 bound the same binding sites in the Il-17a-IL17f locus in CD4+ T cells (113).”
MethodSelf-citationChang, H.-C., Sehra, S., Goswami, R., Yao, W., Yu, Q., Stritesky, G. L., Jabeen, R., McKinley, C., Ahyi, A.-N., Han, L., et al. (2010) · Nature Immunology · doi:10.1038/ni.1867 · Cited by 577
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“Interestingly, functional deletion analysis also identified a silencer element (HS-IV), deletion of which derepressed IL-4 expression (3) and subsequently involvement of T-bet and Runx for the silencer function was revealed (60, 61).”
BackgroundCohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus
Hadjur, S., Williams, L. M., Ryan, N. K., Cobb, B. S., Sexton, T., Fraser, P., Fisher, A. G., & Merkenschlager, M. (2009) · Nature · doi:10.1038/nature08079 · Cited by 525 · cited 2×
“The binding of CTCF (CCCTC-binding factor) and its partners is typically associated with the presence of insulator elements, and the boundaries of the Ifng and IFNG loci are associated CTCF binding (54, 55).”
BackgroundEpigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage?
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“Recently, it was reported that one key role of FoxP3 is to repress the genome organizer protein, SATB1.”
BackgroundInfluentialSelective miRNA disruption in T reg cells leads to uncontrolled autoimmunity
Zhou, X., Jeker, L. T., Fife, B. T., Zhu, S., Anderson, M. S., McManus, M. T., & Bluestone, J. A. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20080707 · Cited by 520
T Helper Cell Fate Specified by Kinase-Mediated Interaction of T-bet with GATA-3
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“T-bet is phosphorylated by Itk, and phosphorylated T-bet binds and repress Gata3, thereby interfering with the Gata3’s function (12).”
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“T-bet also inhibits the function of Gata3 and Rorc, thereby antagonizing Th2 and Th17 differentiation.”
BackgroundInfluentialDeterminants and dynamics of genome accessibility
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“These nucleosome remodelers are multi-protein complexes that employ ATP hydrolysis to slide or disassemble histone octamers (43).”
BackgroundThe Reality of Pervasive Transcription
Clark, M. B., Amaral, P., Schlesinger, F. J., Dinger, M. E., Taft, R. J., Rinn, J. L., Ponting, C. P., Stadler, P. F., Morris, K. V., Morillon, A., et al. (2011) · PLoS Biology · doi:10.1371/journal.pbio.1000625 · Cited by 461
Foxo Transcription Factors Control Regulatory T Cell Development and Function
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“Foxo family members, Foxo1 and Foxo3, also participate in specifying Treg developmental pathway (21).”
BackgroundLong-range intrachromosomal interactions in the T helper type 2 cytokine locus
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“Such interactions can occur in cis in a linear fashion on the same chromosome, as reported for the Th2 cytokine locus and Th2 locus control region (LCR) in T cells (49).”
BackgroundTranscription factories: gene expression in unions?
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“Such functional units have been termed transcription factories (51) and potentially provide a mechanism for co-regulation of diverse genes on different chromosomes.”
BackgroundChIP-Seq identification of weakly conserved heart enhancers
Blow, M. J., McCulley, D. J., Li, Z., Zhang, T., Akiyama, J. A., Holt, A., Plajzer-Frick, I., Shoukry, M., Wright, C., Chen, F., et al. (2010) · Nature Genetics · doi:10.1038/ng.650 · Cited by 392 · cited 1×
“The advent of next generation sequencing has provided an “enhancer signaure” to look for, namely monomethylation of histone H3 lysine 4 (H3K4me1) in the absence of trimetylation (H3K4me3) (118-120) and binding of p300 histone acetyltransferase (116, 121-123).”
BackgroundThe Transcription Factor c-Maf Controls the Production of Interleukin-4 but Not Other Th2 Cytokines
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“GATA3 in turn induces c-Maf, which promotes Th2 differentiation; however, c-Maf deficiency does not abrogate production of Th2 cytokines other than IL-4, suggesting a selective role of c-Maf in regulating IL-4 transcription (14).”
BackgroundPhysical and Functional HAT/HDAC Interplay Regulates Protein Acetylation Balance
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“Histone acetylation is also important for chromatin function and gene transcription, and two classes of antagonizing enzymes contribute to creating and removing these marks, namely histone acetyltransferases (HATs) and deacetylases (HDACs), respectively (31).”
BackgroundDicer-dependent microRNA pathway safeguards regulatory T cell function
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Polycomb Group Protein Ezh2 Controls Actin Polymerization and Cell Signaling
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“In addition though, EZH2 has an extra-nuclear function in that it associates with cytosolic protein complex and controls T cell receptor-induced actin polymerization (79).”
BackgroundThe super elongation complex (SEC) and MLL in development and diseasePreprint
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“In particular, two histone methylation marks at H3K4 and H3K27 represent opposite functions, active chromatin versus silenced chromatin, and they are associated with trithorax (27) and polycomb (28) complexes, respectively, that are responsible to “write” those marks through the catalytic subunit, methytransferases ML…”
BackgroundHegazy, A. N., Peine, C., Helmstetter, C., Panse, I., Fröhlich, A., Bergthaler, A., Flatz, L., Pinschewer, D. D., Radbruch, A., & Löhning, M. (2010) · Immunity · doi:10.1016/j.immuni.2009.12.004 · Cited by 341 · cited 1×
“They showed that committed Gata-3+Th2 cells that are adoptively transferred into virallyinfected mice are reprogrammed to adopt Gata-3+T-bet+ and IL-4+IFN-γ+ phenotypes (10).”
BackgroundWei, L., Vahedi, G., Sun, H., Watford, W. T., Takatori, H., Ramos, H. L., Takahashi, H., Liang, J. Z., Gutierrez-Cruz, G., Zang, C., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.06.003 · Cited by 332 · cited 3×
“2) through comparative analysis of wild type- versus STAT4 knock out cells (104).”
BackgroundSelf-citationRegulation of MicroRNA Expression and Abundance during Lymphopoiesis
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“It is well established that IL-2 inhibits Th17 differentiation and by acting as IL-2 “sinks” Treg cells can promote Th17 differentiation (110-112).”
BackgroundIntegrating 5-Hydroxymethylcytosine into the Epigenomic Landscape of Human Embryonic Stem Cells
Szulwach, K. E., Li, X., Li, Y., Song, C., Han, J. W., Kim, S., Namburi, S., Hermetz, K. E., Kim, J. J., Rudd, M. K., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002154 · Cited by 301 · cited 1×
“The genome-wide distribution of 5-hydroxymethylcytosine (5hmC) showed deposition of the mark in transcribed regions, transcription start sites and a subset of enhancer regions (38, 39).”
BackgroundSharma, S., Findlay, G. M., Bandukwala, H. S., Oberdoerffer, S., Baust, B., Li, Z., Schmidt, V. A., Hogan, P. G., Sacks, D. B., & Rao, A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019711108 · Cited by 296
Cell type–specific DNA methylation at intragenic CpG islands in the immune systemPreprint
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RNA sequencing reveals two major classes of gene expression levels in metazoan cells
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“In addition, global mRNA expression is also profiled with deep sequencing approach (RNA-seq)(84) with many cell types including T cells (85, 86).”
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“Maintenance of IL-17 production requires continued expression of Rorc provided through STAT3 activating signals such as IL-6, IL-23 and IL-21 and inhibition of expression of T-bet and GATA3 (1, 107).”
BackgroundInfluentialPromoter-associated RNA is required for RNA-directed transcriptional gene silencing in human cells
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Self-citationGene regulation by nucleosome positioning
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“Most genomic DNA in eukaryotes is incorporated into nucleosomes and folded in a tightly compacted fashion(41).”
BackgroundChIP‐based methods for the identification of long‐range chromatin interactions
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“Since chromatin interactions captured by chromatin proximity ligation are screened with chromatin IP, and not by any specific bait, ChIA-PET is an unbiased genomewide approach for de novo detection of chromatin interactions mediated by a specific protein, collectively named as interactosome (100).”
BackgroundReciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes
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“Targeted mutation of BAF57 (a component of SWI/SNF complex) resulted in dysregulation of CD4+ gene silencing in T cells (47).”
BackgroundMethodRossi, R. L., Rossetti, G., Wenandy, L., Curti, S., Ripamonti, A., Bonnal, R. J. P., Birolo, R. S., Moro, M., Crosti, M., Gruarin, P., et al. (2011) · Nature Immunology · doi:10.1038/ni.2057 · Cited by 247
Repression of interleukin-4 in T helper type 1 cells by Runx/Cbfβ binding to the Il4 silencer
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“Interestingly, functional deletion analysis also identified a silencer element (HS-IV), deletion of which derepressed IL-4 expression (3) and subsequently involvement of T-bet and Runx for the silencer function was revealed (60, 61).”
BackgroundThe Transcription Factor STAT3 Is Required for T Helper 2 Cell Development
Stritesky, G. L., Muthukrishnan, R., Sehra, S., Goswami, R., Pham, D., Travers, J. B., Nguyen, E., Levy, D. E., & Kaplan, M. H. (2011) · Immunity · doi:10.1016/j.immuni.2010.12.013 · Cited by 241 · cited 1×
“Additionally, STAT3 has been found to be a contributor to Th2 differentiation (15).”
BackgroundEnvironmental epigenetics of asthma: An update
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Regulation of the Th2 Cytokine Locus by a Locus Control Region
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“Transgenic expression of a 30 kb construct encompassing the Il4 and Il3 genes did not exhibit appropriate regulated expression, whereas a construct containing ~25 kb downstream of RAD50 revealed the presence of a locus control region (LCR)(58).”
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“Treg cell specific deletion of a transcription factor critical for other effector lineage, namely IRF4 for Th2 and Stat3 for Th17 cells, suggests that Treg cells elicit effector response-specific suppression by using components of the transcriptional machinery important for the “target” effector lineage (22, 23).”
BackgroundInfluentialThe nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells
Sekiya, T., Kashiwagi, I., Inoue, N., Morita, R., Hori, S., Waldmann, H., Rudensky, A. Y., Ichinose, H., METZGER, D., Chambon, P., et al. (2011) · Nature Communications · doi:10.1038/ncomms1272 · Cited by 215 · cited 1×
“Nrfa2 is yet another factor that positively regulates FoxP3 expression (20).”
Gene Silencing Quantitatively Controls the Function of a Developmental trans-Activator
Hutchins, A. S., Mullen, A. C., Lee, H. W., Sykes, K. J., High, F. A., Hendrich, B., Bird, A. P., & Reiner, S. L. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00564-6 · Cited by 211 · cited 1×
“Conditional ablation of DNMT1 (DNA methyltransferase)(71, 72) or MbD2 (methyl-CpG binding domain protein 2)(73) led to increased expression of IFN-γ and Th2-type cytokines and inability of Th1 or Th2 cells to properly silence the expression of opposing cytokine genes.”
BackgroundMaintaining Cell Identity through Global Control of Genomic Organization
Natoli, G. (2010) · Immunity · doi:10.1016/j.immuni.2010.07.006 · Cited by 208 · cited 1×
“Until recently, evidence of enhancer function relied primarily on conservation (and therefore denoted conserved noncoding sequences or CNS) and DNase hypersensitivity sites (116, 117).”
BackgroundYoung, H. A., Ghosh, P., Ye, J., Lederer, J. A., Lichtman, A. H., Gerard, J. R., Penix, L. A., Wilson, C. B., Melvin, A. J., McGurn, M. E., et al. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.153.8.3603 · Cited by 204 · cited 24×
“One way it seems to work is by dampening expression of T-bet, GATA3, IFN-γ and other factors that allow Th17 cells to drift to become Th1 cells (109).”
BackgroundInfluentialRunx-CBFβ complexes control expression of the transcription factor Foxp3 in regulatory T cells
Rudra, D., Egawa, T., Chong, M. M. W., Treuting, P. M., Littman, D. R., & Rudensky, A. Y. (2009) · Nature Immunology · doi:10.1038/ni.1795 · Cited by 202
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Pol II and its associated epigenetic marks are present at Pol III–transcribed noncoding RNA genes
Barski, A., Chepelev, I., Liko, D., Cuddapah, S., Fleming, A. B., Birch, J. L., Cui, K., White, R. J., & Zhao, K. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1806 · Cited by 191 · cited 1×
“In addition, global mRNA expression is also profiled with deep sequencing approach (RNA-seq)(84) with many cell types including T cells (85, 86).”
MethodIdentifying gene regulatory elements by genome-wide recovery of DNase hypersensitive sites
Crawford, G. E., Holt, I. E., Mullikin, J. C., Tai, D. S., Green, E. D., Wolfsberg, T. G., & Collins, F. S. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307540100 · Cited by 184 · cited 1×
“Genomic sequencing of free ends generated by DNAsemediated cutting identified hypersensitivity sites across the genome, in particular for distal intergenic regulatory elements with open chromosome configuration (89, 90).”
BackgroundChromatin remodeling complexes: strength in diversity, precision through specialization
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“There are several classes of chromatin remodelers, including the SWI/SNF (BAF), ISWI, INO80, SWR, and Mi-2/CHD, each specialized for a different function that can positively or negatively regulate transcription (46, 47).”
MethodPhenotype Switching by Inflammation-Inducing Polarized Th17 Cells, but Not by Th1 Cells
Shi, G., Cox, C. A., Vistica, B. P., Tan, C., Wawrousek, E. F., & Gery, I. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.10.7205 · Cited by 157 · cited 1×
“Extended culture of Th17 cells in vitro or upon adoptive transfer can result in loss of IL-17 production and acquisition of IFN-γ production (107-109).”
BackgroundEZH2 and Histone 3 Trimethyl Lysine 27 Associated with Il4 and Il13 Gene Silencing in TH1 Cells
Koyanagi, M., Baguet, A., Martens, J. H. A., Margueron, R., Jenuwein, T., & Bix, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504766200 · Cited by 155 · cited 1×
“EZH2, a major H3K27 methyltransferase, binds to and suppresses the Il4/Il13 locus in Th1 cells (78).”
BackgroundChi, T. H., Wan, M., Lee, P. P., Akashi, K., METZGER, D., Chambon, P., Wilson, C. B., & Crabtree, G. R. (2003) · Immunity · doi:10.1016/s1074-7613(03)00199-7 · Cited by 155 · cited 1×
“Brahma-related gene 1 (BRG1) is a catalytic subunit of SWI/SNF remodeling complexes and T cell specific deficiency of Brg1 in mice resulted in both thymic and peripheral abnormalities of T cells (80, 81).”
BackgroundPrimer: epigenetics of autoimmunity
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Crucial Role of MLL for the Maintenance of Memory T Helper Type 2 Cell Responses
Yamashita, M., Hirahara, K., Shinnakasu, R., Hosokawa, H., Norikane, S., Kimura, M. Y., Hasegawa, A., & Nakayama, T. (2006) · Immunity · doi:10.1016/j.immuni.2006.03.017 · Cited by 153 · cited 1×
“Haplo-insufficiency of the H3K4 methyltransferase MLL (MLL+/−), the catalytic subunit of Trithorax group (TrxG), resulted in defective maintenance but not initial induction of Il4, Il5, Il13 and Gata3 expression in Th2 cell, indicating its crucial role for memory Th2 cell maintenance (74).”
BackgroundSelf-citationSekimata, M., Pérez‐Melgosa, M., Miller, S. A., Weinmann, A. S., Sabo, P. J., Sandstrom, R. S., Dorschner, M. O., Stamatoyannopoulos, J. A., & Wilson, C. B. (2009) · Immunity · doi:10.1016/j.immuni.2009.08.021 · Cited by 149 · cited 3×
“Based on the recruitment of CTCF/Rad21, the murine Ifng locus extends from −70 to +66 kb relative to the transcription start site (55, 57).”
BackgroundActive recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells
Makar, K. W., Pérez‐Melgosa, M., Shnyreva, M., Weaver, W. M., Fitzpatrick, D. R., & Wilson, C. B. (2003) · Nature Immunology · doi:10.1038/ni1004 · Cited by 147 · cited 1×
“Conditional ablation of DNMT1 (DNA methyltransferase)(71, 72) or MbD2 (methyl-CpG binding domain protein 2)(73) led to increased expression of IFN-γ and Th2-type cytokines and inability of Th1 or Th2 cells to properly silence the expression of opposing cytokine genes.”
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“Publis This is an open access article under the CC BY license (http://creative feron (IFN)-g-producing Th1 cells, interleukin (IL)-4-producing Th2 cells, and IL-17-producing Th17 cells, respectively (Kanno et al., 2012; Littman and Rudensky, 2010).”
Background
Metadata
- Authors
- Kanno, Y., Vahedi, G., Hirahara, K., Singleton, K., & O'Shea, J. J.
- Affiliations
- National Institutes of Health (US)
- Molecular Immunology and Inflammation Branch, National Institutes of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892;
- Venue
- Annual Review of Immunology
- Publisher
- Annual Reviews
- Published
- 2012-04-23
- Volume
- 30
- Issue
- 1
- Pages
- 707-731
- ISSN
- 0732-0582 (ISSN-L)
- 1545-3278
- PMC
- PMC3314163
- OpenAlex
- W2095649879
- Cited by
- 342
- References
- 163
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 12 · 2023: 10 · 2022: 16 · 2021: 19 · 2020: 13 · 2019: 21 · 2018: 22 · 2017: 33 · 2016: 34 · 2015: 49 · 2014: 45 · 2013: 40 · 2012: 9
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annual Review of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99‐AA999999, Z99 AR999999, Z99 DA999999)
- 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 helper cell differentiation, transcription factors, chromatin modification, epigenetics, STAT signaling, T cell receptor signaling, cytokine signaling, T cell transcriptome, T cell plasticity, signal transduction
- MeSH terms
- Animals, Autoimmune Diseases, Cell Differentiation, Gene Expression Regulation, T-Lymphocytes, Helper-Inducer, Humans, Transcription Factors, Transcription, Genetic, Cell Lineage, RNA, Untranslated, Epigenesis, Genetic, Regulatory Elements, Transcriptional, Epigenomics
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