Transcriptional and Epigenetic Control of T Helper Cell Specification: Molecular Mechanisms Underlying Commitment and Plasticity

Abstract

Helper T cell differentiation occurs in the context of the extracelluar 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 like the signal transducer and activator of transcriptions (STATs) that sense the extracellular environment. The acquisition of distinctive transcriptome is also dependent upon 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.

Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation

“…In contrast, the genes encoding the lineage-specifying factors Gata3 (GATAbinding protein 3) and Runx3 (runt-related transcription factor 3) showed a different behavior, reflecting the fact that they act not only in the thymus but also in the periphery. Gata3 is necessary for the DP-to-SP transition (40), for Th2 differentiation (22,24) and for CD8 + T-cell homeostasis and proliferation (41,42). Levels of 5hmC over the Gata3 gene were high, as expected, in CD4 SP cells and Th2 cells, which have high Gata3 expression, but were also high in naive CD4 T cells, the immediate precursors of Th2 cells, and in naive CD8 + T cells, both of which show much lower Gata3 gene expression (Fig.…”

“…Because the thymus contains multiple cell types at different stages of T-cell lineage specification, isolation and analysis of individual cell types provides a snapshot of the transcriptional and epigenetic changes that mark specific developmental transitions. Moreover, the transcription factors that drive these processes of lineage specification have been extensively studied (21)(22)(23)(24). We have mapped the genome-wide distribution of 5hmC in selected thymic and peripheral T cells and have analyzed its correlation with other Significance 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification produced through the enzymatic activity of TET proteins.…”

The tumor microenvironment disarms CD8+ T lymphocyte function via a miR-26a-EZH2 axis

“…16 Also, activation of STAT3 in CTLs by multiple TME growth factors and cytokines directly antagonize type-I immunity. 17 Epigenetic regulation carried out by DNA methylation and histone modification represents another fundamental regulatory mechanism 18 in the TME to blunt CTL activity. Polycomb group protein EZH2 is one such essential epigenetic regulator, which catalyzes trimethylation of H3K27 and acts primarily as a transcription silencer.…”

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

“…Although lineage-specific transcription factors are key regulators of helper T-cell differentiation, epigenetic modifications, such as the methylation of DNA and posttranslational modifications of histones, also play crucial roles (14,15). Trithorax group (TrxG) and Polycomb group (PcG) genes were originally discovered in Drosophila melanogaster as activators and repressors of Homeobox genes, respectively (16).…”