Abstract
Maps of Hi-C contacts between promoters and enhancers can be analyzed as networks, with cis-regulatory regions as nodes and their interactions as edges. We checked if in the published promoter–enhancer network of mouse embryonic stem (ES) cells the differences in the node type (promoter or enhancer) and the node degree (number of regions interacting with a given promoter or enhancer) are reflected by sequence composition or sequence similarity of the interacting nodes. We used counts of all k-mers (k = 4) to analyze the sequence composition and the Euclidean distance between the k-mer count vectors (k-mer distance) as the measure of sequence (dis)similarity. The results we obtained with 4-mers are interpretable in terms of dinucleotides. Promoters are GC-rich as compared to enhancers, which is known. Enhancers are enriched in scaffold/matrix attachment regions (S/MARs) patterns and depleted of CpGs. Furthermore, we show that promoters are more similar to their interacting enhancers than vice-versa. Most notably, in both promoters and enhancers, the GC content and the CpG count increase with the node degree. As a consequence, enhancers of higher node degree become more similar to promoters, whereas higher degree promoters become less similar to enhancers. We confirmed the key results also for human keratinocytes.
Highlights
It is well known that cis-regulatory regions of metazoans are split into promoters—proximal to transcription start sites (TSSs) and regions distal to TSSs, of which the most studied are enhancers, defined by ability to enhance the expression of genes by interaction with promoters, which typically involves looping out of the intervening chromosome segment [1,2]
We used the data on the mouse embryonic stem (ES) cells, comprising of 94,943 interactions between 15,905 promoters and 71,985 enhancers recently published by Sahlén et al (2015) [4]
The fact that promoters have high G or C (GC) content and often harbor CpG islands (CGIs) is well known [16], and these sequence characteristics are important for establishing nucleosome-free regions [18,19]
Summary
It is well known that cis-regulatory regions of metazoans are split into promoters—proximal to transcription start sites (TSSs) and regions distal to TSSs, of which the most studied are enhancers, defined by ability to enhance the expression of genes by interaction with promoters, which typically involves looping out of the intervening chromosome segment [1,2]. With the establishment and refinement of chromosome conformation capture methods [3,4,5], it has become possible to study promoter–enhancer interactions by loop formation at a genome-wide scale. From such studies, it has become apparent that in the mouse embryonic stem (ES) cells, the majority of enhancers interact over relatively short distance with just one promoter, while promoters typically interact with several enhancers, and there are many enhancers, in particular super-enhancers that interact with multiple promoters [4,6]. We have asked whether the type of the node (promoter vs. enhancer) and its node degree are associated with the sequence characteristics of the interacting promoters and enhancers
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