Epigenetic priming describes the establishment of a competent epigenetic landscape that facilitates efficient transcriptional responses at a future point in time. This temporal uncoupling of molecular events is especially fitting in the context of early development where genes that are not yet expressed need to avoid permanent silencing prevalent in the peri-implantation embryo. Epigenetic priming factors are frequently mis-regulated in cancers, potentially increasing their epigenetic plasticity and contributing to tumorigenesis. However, we know little of the identity of epigenetic priming factors and their mode of action. Understanding how epigenetic priming factors function is key not only to improve our understanding of the tight control of development, but also to give insights into how this goes awry in diseases of cell identity, such as cancer
Our work has identified developmental pluripotency associated 2 (Dppa2) and 4 (Dppa4) as epigenetic priming factors in early embryos. Firstly, using in vitro embryonic stem cell models, we revealed their function as key regulators of the zygotic transcriptional programme by directly regulating the transcription factor Dux. Furthermore, Dppa2/4 also function in pluripotency and are required to maintain both H3K4me3 and H3K27me3 at a set of developmentally important bivalent promoters. As a consequence of losing bivalency, these genes gain DNA methylation and can no longer be effectively activated during differentiation. These epigenetic changes are reversible on reintroduction of Dppa2/4 suggesting that Dppa2/4 are required to actively target and maintain the epigenetic landscape at these developmental genes in pluripotent cells.
Our work illustrates how epigenetic priming factors are important gatekeepers of early embryonic cell fate transitions. Ongoing work explores how developmental epigenetic priming factors, such as Dppa2/4, may be hijacked in cancers to promote cell plasticity and facilitate acquisition of new identities or functions.