Pleiotropic enhancers are ubiquitous regulatory elements in the human genome

Abstract

Enhancers are regulatory elements of genomes that determine spatio-temporal patterns of gene expression. The human genome contains a vast number of enhancers, which largely outnumber protein-coding genes. Classically, enhancers have been regarded as highly tissue-specific. However, recent evidence suggests that many enhancers are pleiotropic, with activity in multiple developmental contexts. Yet, the extent and impact of pleiotropy remain largely unexplored. In this study we predicted active enhancers across human organs based on the analysis of both eRNA transcription (FANTOM5 consortium datasets) and chromatin architecture (ENCODE consortium datasets). We show that pleiotropic enhancers are pervasive in the human genome and that most enhancers active in a particular organ are also active in other organs. In addition, our analysis suggests that the proportion of context-specific enhancers of a given organ is explained, at least in part, by the proportion of context-specific genes in that same organ. The notion that such a high proportion of human enhancers can be pleiotropic suggests that small regions of regulatory DNA contain abundant regulatory information and that these regions evolve under important evolutionary constraints. Significance statementThe human genome contains a vast number of regulatory elements, named enhancers, that control the tempo and mode of gene expression. Classically, enhancers have been regarded as genetic elements that are active in a single organ, but recent evidence suggests that many enhancers in animal genomes are active in multiple organs (i.e., are pleiotropic). Here we shed light on the architecture of non-coding human DNA by showing that a large percentage of the enhancers of the human genome are pleiotropic and that the majority of enhancers active in a particular organ are pleiotropic. This suggests that small regions of regulatory DNA may contain abundant regulatory information and that these regions evolve under important evolutionary constraints.