Enhancer reprogramming in mammalian genomes

Mario A. Flores, Ivan Ovcharenko

Transcription factor binding site (TFBS) loss, gain, and reshuffling within the sequence of a regulatory element could alter the function of that regulatory element. Some of the changes will be detrimental to the fitness of the species and will result in gradual removal from a population, while other changes would be either beneficial or just a part of genetic drift and end up being fixed in a population. This "reprogramming" of regulatory elements results in modification of the gene regulatory landscape during evolution. We identified reprogrammed enhancers (RPEs) by comparing the distribution of tissue-specific enhancers in the human and mouse genomes. We observed that around 30% of mammalian enhancers have been reprogrammed after the human-mouse speciation. In 79% of cases, the reprogramming of an enhancer resulted in a quantifiably different expression of a flanking gene. In the case of the Thy-1 cell surface antigen gene, for example, enhancer reprogramming is associated with cortex to thymus change in gene expression. To understand the mechanisms of enhancer reprogramming, we profiled the evolutionary changes in the TFBS enhancer content and found that enhancer reprogramming took place through the acquisition of new TFBSs in 72% of reprogramming events. Our results suggest that enhancer reprogramming takes place within well-established regulatory loci with RPEs contributing additively to fine-tuning of the gene regulatory program in mammals. We also found evidence for acquisition of novel gene function through enhancer reprogramming, which allows expansion of gene regulatory landscapes into new regulatory domains.