Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity

Abstract

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.

Fig. 1

The mouse Ifng locus and surrounding regulatory regions identified by various chromatin signatures in Th1 cells. CNS denotes the conserved noncoding sequence described previously (1). DNase hypersensitivity sites (DHS) and T-bet binding sites are depicted from genome-wide data available from Gene Expression Omnibus (GEO) under the accession number GSE33802. H3K4me3 denotes trimethylation of lysine 4 on histone 3 that is regarded as permissive histone modification. Locations of H4K4me3 and STAT4 binding sites were depicted from genome-wide data in GEO with the accession number GSE22105. Location of CCCTC-binding factor (CTCF) binding sites was described (1) and also confirmed by genome-wide data (J. J. O., unpublished observation).

Fig.2

How STATs regulate global gene transcription and histone epigenetic modification. Based on genome-wide analysis of STAT binding, histone epigenetic modifications (H3K4me3, H3K27me3, H3K36me3) and gene transcription, the consequences of STAT binding to the target genes are classified into 4 different patterns:

1. Both transcription and local epigenetic status are dependent on STAT

2. Transcription is STAT-dependent but local epigenetic status is not

3. Epigenetic status is STAT-dependent but gene transcription is not

4. Neither transcription nor epigenetic status are STAT-dependent

pie charts on top: Among all the genes bound by STAT proteins (STAT4 bound genes in Th1 condition (left) and STAT6 bound genes in Th2 (right)), proportions of genes that belong to categories A to D are shown; A(red), B(orange), C(yellow), D(gray).