Epigenetic control of T-helper-cell differentiation

Gene expression is regulated by transcription factors in concert with epigenetic modifications (such as DNA methylation, post-translational histone modifications, the position and compaction of nucleosomes and higher-order structural organization) at the gene regulatory elements where these factors can bind. Epigenetic modifications are heritable but plastic, thereby allowing cells to modify their gene expression patterns in response to changing contexts, as CD4+ T cells do in response to infection with different types of pathogen.The pace of discovery in the field of epigenetics is accelerating through the application of new genomic approaches, which are yielding new insights on the gene regulatory mechanisms in T helper (TH) cells and other cell types. Compelling evidence indicates that epigenetic modifications at TH-cytokine and transcription factor gene loci work in concert with lineage-restricted transcription factors to govern cytokine expression and to stabilize lineage commitment.During TH2-cell differentiation, GATA-binding protein 3 (GATA3) is necessary and apparently sufficient to induce TH2-type cytokine expression, as well as most, if not all, of the favourable epigenetic modifications to the TH2-cytokine locus and repressive modifications to the Ifng (interferon-γ) locus. Following these modifications, GATA3 contributes importantly to maintenance of the complete TH2-cell phenotype but is not absolutely essential for the maintenance of Il4 (interleukin-4) expression.T-bet acts in concert with signal transducer and activator of transcription 4 (STAT4) during TH1-cell differentiation to induce IFNg expression and epigenetic remodelling of the Ifng locus, and to repress TH2-cytokine expression directly and through the inhibition of GATA3. The expression of T-bet does not seem to be essential for the maintenance of IFNg expression, but it is required to maintain certain other aspects of the TH1-cell phenotype.The three-dimensional architecture of the TH2-cytokine and Ifng loci is modified by 'chromatin looping', which brings distal gene regulatory elements in proximity with genes they help to regulate in appropriate cell types.Additional work is needed to determine how specific combinations of epigenetic modifications are established by networks of lineage-specifying transcription factors, whether, when and how they can later be removed or selectively modified, and their causal contribution to the stability or plasticity of TH-cell lineage specification.