Naive CD4(+) T cells give rise to T-helper-cell subsets with functions that are tailored to their respective roles in host defence. The specification of T-helper-cell subsets is controlled by networks of lineage-specifying transcription factors, which bind to regulatory elements in genes that encode cytokines and other transcription factors. The nuclear context in which these transcription factors act is affected by epigenetic processes, which allow programmes of gene expression to be inherited by progeny cells that at the same time retain the potential for change in response to altered environmental signals. In this Review, we describe these epigenetic processes and discuss how they collaborate to govern the fate and function of T helper cells.
Unlike the well defined T helper type 2 cytokine locus, little is known about the regulatory elements that govern the expression of Ifng, which encodes the 'signature' T helper type 1 cytokine interferon-gamma. Here our evolutionary analysis showed that the mouse Ifng locus diverged from the ancestral locus as a result of structural rearrangements producing deletion of the neighboring gene encoding interleukin 26 and disrupting synteny 57 kilobases upstream of Ifng. Proximal to that disruption, we identified by high-resolution mapping many regions with CD4+ T cell subset-specific epigenetic modifications. A subset of those regions represented enhancers, whereas others blocked the activity of upstream enhancers or insulated Ifng from neighboring chromatin. Our findings suggest that proper expression of Ifng is maintained through the collective action of multiple distal regulatory elements present in a region of about 100 kilobases flanking Ifng.
How cell type-specific differences in chromatin conformation are achieved, and their contribution to gene expression are incompletely understood. Here we identify a cryptic upstream orchestrator of interferon-γ (Ifng) transcription, which is embedded within the human IL26 gene, compromised of a single CTCF-binding site and retained in all mammals, even surviving near-complete deletion of IL26 in rodents. CTCF and cohesins occupy this element in vivo in a cell-type non-specific manner. This element is approximated with two other sites located within the first intron and downstream of Ifng, where CTCF, cohesins and T-bet bind in a Th1-specific manner. These interactions, approximation of other elements within the locus to each other and to Ifng, and robust Ifng expression are dependent on CTCF and T-bet. The results demonstrate that cooperation between architectural (CTCF) and transcriptional enhancing (T-bet) factors and the elements to which they bind is required for proper Th1-specific expression of Ifng.
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