Transcriptional memory in T cells is maintained by priming elements which create active chromatin domains that enable rapid responses in memory T cells without influencing steady state transcription

Abstract

We have defined epigenetic mechanisms whereby immune response genes are reprogrammed for rapid recall responses when naïve T cells are transformed via TCR signalling into activated T cells. Until recently, distal regulatory elements were typically defined in genome-wide studies as transcriptional enhancers based on the presence of histone H3 K4 methylation and K27 acetylation. However, we and others have found that this definition is too simplistic because many, if not most, such distal regulatory elements appear to lack classical transcriptional enhancer activity. By focusing on previously activated primed T cells, we found that distal regulatory elements can be further subdivided into two distinct sub-classes of gene regulatory elements. Firstly, there are classical enhancers which do indeed appear to function to activate transcription of a nearby gene, and/or the underlying enhancer sequence. Transcriptional enhancers have been observed to function up to a megabase away, most likely by looping to contact a promoter. In addition to these classical enhancers, we have now defined a distinct class of chromatin priming enhancers, which are also modified by H3 K4 methylation and K27 acetylation, but which do not result in any significant change in the levels of transcription of nearby genes or regulatory elements. In memory T cells, these priming elements function to maintain a transcriptional memory which allows inducible immune response genes to be rapidly reactivated. These highly specialised elements function locally to establish active accessible chromatin domains in the vicinity of promoters or transcriptional enhancers, allowing easy access for the recruitment of transcription factors induced by TCR signalling. We recently observed that these priming elements also support T cell differentiation to alternate Th1, Th2 and Th17 lineages by making lineage-specific loci permissive to the transcription factors that direct these lineage switches, such as T-bet, GATA3 and RORg. Rather than establishing new active loci, these factors are often recruited to open chromatin regions established in response to TCR signalling, prior to terminal differentiation.