The essential but enigmatic regulatory role of HERVH in pluripotency

Human specific endogenous retrovirus H (HERVH) is highly expressed in both naive and primed stem cells and is essential for pluripotency. Despite the proven relationship between HERVH expression and pluripotency, there is no single definitive model for the function of HERVH. Instead, several hypotheses of a regulatory function have been put forward including HERVH acting as enhancers, long noncoding RNAs (lncRNAs), and most recently as markers of topologically associating domain (TAD) boundaries. Recently several enhancer-associated lncRNAs have been characterized, which bind to Mediator and are necessary for promoter–enhancer folding interactions. We propose a synergistic model of HERVH function combining relevant findings and discuss the current limitations for its role in regulation, including the lack of evidence for a pluripotency-associated target gene. Human specific endogenous retrovirus H (HERVH) is one of the most recently integrated and most numerous endogenous retroviruses in the human genome. It is highly expressed in stem cells, essential for pluripotency, and long been hypothesized to be an enhancer important in stem cells.Mediator is a dynamic complex that changes conformation and partner proteins to bridge enhancers and promoters and initiate transcription.Long noncoding RNAs (lncRNAs) transcribed from enhancers are shown to be functional participants of the enhancer regulation of target genes. One way that enhancer-associated lncRNAs function is through binding of MED12 and stabilizing the chromatin loops between enhancers and promoters.Crosslinking immunoprecipitation experiments have shown specific binding of HERVH transcripts to MED12 and other Mediator kinase proteins.Highly transcribed HERVH loci are capable of demarcating stem cell specific topologically associating domain (TAD) boundaries and defining 3D chromatin structures. Deleting HERVH elements eliminates TAD boundaries and reduces the transcription of nearby genes.