Super-enhancers delineate disease-associated regulatory nodes in T cells

Abstract

Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity1. Stretch- or super-enhancers (SEs) are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease2,3,4,5,6. CD4+ T cells are critical for host defense and autoimmunity. Herein, we analyzed maps of T cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. This notwithstanding, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T cell SE, revealing a network wherein SE-associated genes critical for T cell biology are repressed by BACH2. Disease-associated SNPs for immune-mediated disorders, including rheumatoid arthritis (RA), were highly enriched for T cell-SEs versus typical enhancers (TEs) or SEs in other cell lineages7. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor, tofacitinib, disproportionately altered the expression of RA risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a “guardian” transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

“…These patterns fit well with other studies, which show similar distributions of signal and enhancer width when applying ATAC-seq and complementary techniques, including p300 and Mediator ChIP-seq, in different tissues (9,12,13). The colonization-independent super-enhancer populations in TCR αβ + and TCR γδ + IELs were highly similar, with a Jaccard similarity index of 83% (Fig.…”

“…Applying the same analytic approach to peripheral circulating T cells revealed that super-enhancers comprised 5.7% of the population but 37.7% of the aggregate ATAC-seq signal [values comparable to those reported in mice and humans (9,12,13,16)]. The superenhancer associated with Bach2 (basic leucine zipper transcription factor 2) produced the top-ranked ATAC-seq signal in CD4 + T cells ( Fig.…”

“…Super-enhancers are a subclass of enhancers that are stronger (more occupied by transcriptional activators) and can span longer regions of DNA than traditional enhancers (9,10). Super-enhancers can drive cell lineagespecific functions and play critical roles in disease pathogenesis (11,12). We identified super-enhancers by first combining adjacent peaks within a 12.5-kb window (the fixed stitching approach described above), ranking and graphing these merged enhancers by their normalized read depth (ATAC-seq signal), and discriminating traditional enhancers from super-enhancers by determining where the slope of a tangent line fitted to their graph reached one (10).…”

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…In the case of autoimmune diseases data sets, there is also significant enrichment of genetic variation in T‐cell‐specific regulatory elements, including promoters and enhancers,106, 107 suggesting that dysregulation of multiple separate pathways in the immune system can result in the same phenotype from unrelated genotypes. In the case of type 1 diabetes, a recent Bayesian analysis of the intersection between genetic risk and regulatory motifs found significant enrichment of snps within enhancer regions,29 suggesting that the consequence of single nucleotide polymorphism may be to alter the expression of multiple target genes.…”

“…Localised patterns of chromatin modification, such as DNA methylation, histone modification and nucleosome remodelling, correlate with enhancer activity, transcription factor binding and initiation or repression of transcription 99, 109, 110. More recently, these approaches have enabled the identification of a rare subset of enhancers, termed super‐enhancers 103, 107. Super‐enhancers are characterised by a relative enrichment of active enhancer‐associated epigenetic marks and transcriptional cofactor binding, and they appear to regulate key genes involved in cell type‐specific function 103, 107…”