Endogenous retroviruses (ERVs) arise from germline invasion of their exogenous counterparts. Once integrated, ERVs can be inherited to subsequent generations. With potentially pathogenic effects, ERVs are generally repressed by their hosts through epigenetic mechanisms, including DNA methylation and histone modifications. However, throughout evolution, a portion of ERV elements have been coopted to exert particular functions for the host genome, as coding genes and cis-regulatory elements. It was previously reported that several ERV families exhibit stage-specific activity in early embryonic development. In this study, we aimed to delineate the potential functions and regulatory pathways of ERVs in mammalian pluripotent cells. We analyzed the differential transcriptional patterns of ERV...[ Read more ]

Endogenous retroviruses (ERVs) arise from germline invasion of their exogenous counterparts. Once integrated, ERVs can be inherited to subsequent generations. With potentially pathogenic effects, ERVs are generally repressed by their hosts through epigenetic mechanisms, including DNA methylation and histone modifications. However, throughout evolution, a portion of ERV elements have been coopted to exert particular functions for the host genome, as coding genes and cis-regulatory elements. It was previously reported that several ERV families exhibit stage-specific activity in early embryonic development. In this study, we aimed to delineate the potential functions and regulatory pathways of ERVs in mammalian pluripotent cells. We analyzed the differential transcriptional patterns of ERVs, especially LTR12C elements, during early embryonic cell differentiation in in vitro models. Moreover, we characterized the function of individual LTR12C elements in human embryonic stem cells (hESCs). On the other hand, we discovered the role of the RIF1 protein in repressing human ERVs (HERVs) in hESCs. Our results showed that RIF1 silenced specific HERVs, in concert with repressive histone modifications. Furthermore, utilizing mouse embryonic stem cell (mESC) lines from distinct backgrounds, we demonstrated that a naturally occurring polymorphic GLN element resulted in the intra-species transcriptomic diversity through regulating the expression of its nearby gene, Klhdc4. Interestingly, although the function of Klhdc4 is largely unknown, we discovered its dysregulation was associated with stress response pathways. Finally, we defined potential polymorphic ERVs (ppERVs) in two mESC lines and studied their potential role in regulating differential chromatin state and transcriptional activity of neighboring genomic regions. Taken together, this study emphasized the significance of ERVs in mammalian pluripotent cells.