The essential but enigmatic regulatory role of HERVH in pluripotency

Abstract

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.

Keywords: endogenous retrovirus; enhancer; gene regulation; mediator, topologically associating domain (TAD); stem cell.

Figure 1.

HERVH long noncoding RNA (lncRNA; represented by the orange line) is an activating enhancer-associated lncRNA that binds to Mediator kinase and OCT4, contributing to the loop between long terminal repeat (LTR7), which acts as an enhancer, and the target promoter. Additionally, RNA polymerase II and CCCTC-binding factor (CTCF) accumulate at the 3' end of the HERVH sequence, corresponding with topologically associating domain (TAD) boundaries. Chromatin immunoprecipitation sequencing (ChIP-Seq) analysis is represented by triangles, RNA crosslinking immunoprecipitation (RNA-CLIP) evidence is represented by lines and circles, and Hi-C contact is represented by the circular cohesin loop and black DNA line.