Evolution of Alu Elements toward Enhancers

Summary: The human genome contains approximately one million Alu repetitive elements comprising 10% of the genome, yet their functions are not well understood. Here, we show that Alu elements resemble enhancers. Alu elements are bound by two well-phased nucleosomes that contain histones bearing marks of active chromatin, and they show tissue-specific enrichment for the enhancer mark H3K4me1. A proportion of Alu elements were experimentally validated as bona fide active enhancers with an in vitro reporter assay. In addition, Hi-C data indicate that Alus show long-range interactions with gene promoters. We also find that Alus are generally more conserved when located in the proximal upstream region of genes. Their similarity to enhancers becomes more prominent with their age in the human genome, following a clear evolutionary continuum reminiscent of the evolutionary pattern of proto-genes. Therefore, we conclude that some Alu elements can function as enhancers and propose that many more may be proto-enhancers that serve as a repertoire for the de novo birth of enhancers. : Despite comprising 10% of the human genome, the functions of Alu elements are uncertain. Su et al. found that Alus have enhancer-like genomic distribution, tissue-specific epigenetic profiles, enrichment for transcription factor binding motifs, and evolutionary conservation; furthermore, these features become more prominent with their age in the human genome, following a clear evolutionary continuum. This is reminiscent of the evolutionary pattern of proto-genes, thus supporting Alu elements as proto-enhancers that serve as a repertoire for the de novo birth of enhancers