Epigenetic relay: Polycomb-directed DNA methylation in mammalian development

In mammals, repression of germline-specific gene expression is essential for preserving somatic cell identity and preventing disease. Germline gene silencing is often dependent on the presence of promoter 5-cytosine DNA methylation (5meC). Early mammalian development, however, is marked by a dramatic loss of 5meC levels genome-wide. Recent research has highlighted a specialized variant of the Polycomb Repressive Complex 1, PRC1.6, as a key regulator that maintains transient silencing of germline genes in this embryonic window. Eventually, PRC1.6 seems to stimulate the recruitment of de novo DNA methyltransferases (DNMTs), although the precise mechanisms remain to be fully elucidated. Evidence suggests a coordinated epigenetic relay, potentially involving direct protein interactions and shaping the local histone modification landscape. This review explores PRC1.6 as a central epigenetic hub that connects Polycomb repression, histone 3 lysine 9 (H3K9) methylation, and DNA methylation pathways. Unraveling this interplay will provide key insights into the mechanisms that maintain the critical barrier between the germline and the soma, essential not only for proper development but also for preserving somatic cell function and health throughout life.