Supplementary Figure 8: Tissue-specific enhancer hubs.

a, Multiple logistic regression analysis was used to identify PAT features that predict islet-expressed genes with islet-selective vs. non islet-selective expression. Islet-selective expression was examined as a surrogate endpoint because it is a property of many (though not all) genes important for islet cell identity. The PAT feature with the highest logistic regression coefficient was the number of non-islet tissues with promoter H3K27me3-enrichment. This feature was considered as almost synonymous with islet-specific islet expression. The next highest coefficient was the number assigned class I enhancers in the PAT. Further analysis showed that ≥3 assigned class I enhancers in a PAT optimized the prediction of islet-selective expression (Supplementary Fig. 9). b, Classification of PATs based on assigned enhancers revealed 2,623 enhancer-rich PATs (≥3 assigned class I enhancers). Enhancers are shown as red boxes. Turquoise and dashed green lines are high-confidence interactions and imputed assignments, respectively. c, Enhancer hubs were defined as enhancer-rich PATs, which were merged with other PATs connected through at least one common enhancer-associated high-confidence interaction. d, Descriptive characteristics of enhancer hubs in human islets. Multi-target enhancers show high confidence interactions with two or more promoter-containing baits. e, Enhancer hubs are enriched in islet-selective interactions relative to non-hub PATs that had at least 1 high-confidence interaction. Boxes are IQR, notches are 95% CI of the median and P values are from Wilcoxon’s two-sided signed rank test. f, Linear genomic space occupied by class I enhancers in three-dimensional enhancer hubs compared with the space occupied by super-enhancers (SEs) calculated with the ROSE algorithm, all enhancers from linear enhancer clusters (ECs), and stretch enhancers. g-i. Venn diagrams depicting how often hub enhancers overlap with other human islet enhancer domains: g, SEs, h, highly-bound (top two TF occupancy quartiles) ECs, and i, stretch enhancers. j-l. Islet enhancer hubs often contain enhancers that do not form part of SEs or ECs. Charts show the fraction of hub class I enhancers that overlapped SEs, ECs or stretch-enhancers. Note that the genomic space occupied by stretch enhancers is an order of magnitude greater than hubs (panel g). m-o. Islet enhancer hubs very frequently contain multiple SEs, ECs or stretch enhancers.