Transcriptional and epigenetic regulation of T-helper lineage specification.
Bottom Line: Combined with TCR stimuli, extracellular cytokine signals initiate the differentiation of naive CD4(+) T cells into specialized effector T-helper (Th) and regulatory T (Treg) cell subsets.The lineage specification and commitment process occurs through the combinatorial action of multiple transcription factors (TFs) and epigenetic mechanisms that drive lineage-specific gene expression programs.Moreover, we review current study linking immune disease-associated single-nucleotide polymorphisms with distal regulatory elements and their potential role in the disease etiology.
Affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; National Doctoral Programme in Informational and Structural Biology, Turku, Finland; Turku Doctoral Programme of Molecular Medicine (TuDMM), University of Turku, Turku, Finland.Show MeSH
Mentions: Genome-wide studies have identified targets of STATs shaping the gene expression programs topromote differentiation of specific Th cell-lineages while opposing alternative fates 23,80–82. These studies have revealed that around 20% of theSTAT-binding sites are in the promoters, whereas over 70% of them are in the intergenic andintronic regions. These results suggest that STATs utilize these cis-regulatoryelements to regulate gene expression in relevant Th subsets. It remains an open question what arethe factor(s) involved in establishing the lineage-specific epigenetic status in Th cells. Asepigenetic status of a cell can be changed in response to environmental factors (for examplestimulation with environmental cytokine milieu), STATs as sensors of environmental cytokines andamplifiers of the Th-cell differentiation are candidates for shaping the chromatin landscape indifferentiating Th cells. Recent studies suggest that aside from directing transcription throughbinding to cis-regulatory elements, STATs regulate epigenetic landscape byinfluencing the histone modification status of the cell at these regulatory regions 7,10,11,23,80,82. Further, genome-wide analysis revealed thatSTAT3 and STAT4 have influence on active promoter mark, H3K4me3 10,80,82.Conversely, STAT6 has been shown to affect H3K27me3 status 82. In the recent past, much of the focus has been on these distal regulatory enhancerelements in instructing lineage-specific gene expression programs in various cells including T cells10,11,46,52. STAT1 and STAT4participate in creating sites for enhancers in differentiating Th1 cells 106,295,296. STATs were also shown to alter the repressive histone modification state into activehistone modification state at these enhancer sites 10. On thebasis of ChIP analysis of subsets of Th2-specific enhancers identified from global analysis, weshowed that these enhancers were already marked with H3K4me1 and STAT6 binding at early stage ofdifferentiation while they gained H3K27ac at a later stage of Th2 development. This indicate thatmarking of enhancers and binding of STAT6 to these enhancers takes place first while they becomefully active at the later stage differentiation 11. Thus,STATs may have function in shaping enhancer repertoire for lineage-specific TFs and enable them tobind at these enhancers to regulate expression of genes (Fig. 4). Also, these studies have suggested that STATs play animportant role in guiding lineage-specific gene expression programs through multiple mechanisms thatcause changes in global gene transcription and histone epigenetic modifications.
Affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; National Doctoral Programme in Informational and Structural Biology, Turku, Finland; Turku Doctoral Programme of Molecular Medicine (TuDMM), University of Turku, Turku, Finland.