Genome-Wide Analysis of Functional and Evolutional Features of Tele-Enhancers

Function and evolution of tele-enhancers ABSTRACT We investigated discriminating features between enhancers separated from their target genes by at least one intermediate gene/exon (named tele-enhancers in this study) and enhancers residing inside the target gene locus. In this study, we used genome-scale enhancer maps and whole-genome gene expression profiles to establish a large panel of heart tele-enhancers. By contrasting tele-enhancers to proximal heart enhancers located in the neighborhood of heart genes, we observed that heart tele-enhancers employ unique regulatory mechanisms based on cardiac transcription factor SRF, TEAD, and NKX-2.5, while proximal heart enhancers rely on GATA4 factors. A functional analysis shows that tele-enhancers preferentially regulate housekeeping genes and play a metabolic role during heart development. In addition, with 1) lower nucleotide divergence, 2) lower single-nucleotide polymorphism (SNP) density, and 3) smaller proportion of low derived-allele-frequency SNPs, tele-enhancers are significantly more conserved than their proximal counterparts. Similar trends have been observed in non-heart tissues and cell types, suggesting that our findings are general characteristics of tele-enhancers.