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Genome-wide Identification and Analysis of Enhancer Regulated microRNAs Across 31 Human Tissues

Enhancers are cis-regulatory DNA elements that positively regulate the transcription of target genes in a tissue-specific manner and dysregulation in various diseases such as cancer. Recent studies shown that enhancers could regulate miRNAs and participate in the biological synthesis of miRNAs. However, the network of enhancer-regulated miRNAs across multiple cancers are still unclear. Here, we identified a total of 2,418 proximal enhancer-miRNA interactions and 1,280 distal enhancer-miRNA interactions through integration of genomic distance, co-expression and 3D genome data in 31 cancers. The results shown that both proximal and distal interactions exhibit significantly tissue-specific feature and there is a significant positive correlation between the expression of miRNA and the number of regulated enhancers in most tissues. Furthermore, we found that there is a high correlation between the formation of enhancer-miRNA pairs and expression of eRNAs whether in distal or proximal regulation. The characteristics analysis shown that miRes (enhancers that regulated miRNAs) and non-miRes presented significantly different in sequence conservation, GC content and histone modification signatures. Notably, GC content, H3K4me1, H3K36me3 present different between distal regulation and proximal regulation suggesting they may participate in chromosome looping of enhancer-miRNA interactions. Finally, we introduced a case study, enhancer: chr1:1186391-1186507∼miR-200a was highly relevant with survival of thyroid cancer patients and a cis-eQTL SNP on enhancer effect the expression TNFRSF18 gene as a tumor suppressor.