An intriguing characteristic of enhancer-promoter interactions

Abstract

Background: It is still challenging to predict interacting enhancer-promoter pairs (IEPs), partially because of our limited understanding of their characteristics. To understand IEPs better, here we studied the IEPs in nine cell lines and nine primary cell types.

Results: By measuring the bipartite clustering coefficient of the graphs constructed from these experimentally supported IEPs, we observed that one enhancer is likely to interact with either none or all of the target genes of another enhancer. This observation implies that enhancers form clusters, and every enhancer in the same cluster synchronously interact with almost every member of a set of genes and only this set of genes. We perceived that an enhancer can be up to two megabase pairs away from other enhancers in the same cluster. We also noticed that although a fraction of these clusters of enhancers do overlap with super-enhancers, the majority of the enhancer clusters are different from the known super-enhancers.

Conclusions: Our study showed a new characteristic of IEPs, which may shed new light on distal gene regulation and the identification of IEPs.

Keywords: Enhancer clusters; Enhancers; Promoters; Super-enhancers.

Fig. 1

a The process of generating IEPs using the chromatin interaction data from five studies, enhancer regions from FANTOM and ChromHMM and promoters defined around the GENCODE annotated gene TSSs. b An toy interaction network between three enhancers (e₁, e₂ and e₃) and three promoters (p₁, p₂ and p₃). The average BCC of the enhancers in this example is $\frac{\frac{1}{2}+\frac{7}{12}+\frac{5}{12}}{3}=0.5$

Fig. 2

Clusters of enhancers with Hi-C reads. Here all ChromHMM active enhancer clusters in GM12878 are shown within the region Chr1:161,060,000-161,175,000. Total five clusters belong to this region. The bottom half of the figure shows the five enhancer clusters (grey, yellow, green, purple and brown on the two sides) interacting with the common gene promoter regions (in the middle), arranged from left to right according to their relative genomic locations. The top half of the figure shows the same interactions of the five clusters (same color codes) with Hi-C reads. For example, the yellow cluster of enhancers interact with NIT1 and PFDN2 gene promoters with 687 Hi-C reads. The unmarked enhancer (blue) and gene promoter (UFC1) did not belong to any cluster. The location of the enhancers relative to each other and to the target genes are shown in the middle

Fig. 3

The distance distribution between consecutive enhancers in the same cluster for each cell line. The X-axis represents the distance and the Y-axis represents the average percentage of consecutive enhancer pairs in an enhancer cluster

Fig. 4

The overlap of the enhancer clusters with the super-enhancers. a The percentage of the enhancer clusters overlapping with the super-enhancers. b The percentage of the super-enhancers overlapping with the enhancer clusters