How the epigenetic landscape is established in development is still being elucidated. Here, we uncover developmental pluripotency associated 2 and 4 (DPPA2/4) as epigenetic priming factors that establish a permissive epigenetic landscape at a subset of developmentally important bivalent promoters characterized by low expression and poised RNA-polymerase. Differentiation assays reveal that Dppa2/4 double knockout mouse embryonic stem cells fail to exit pluripotency and differentiate efficiently. DPPA2/4 bind both H3K4me3-marked and bivalent gene promoters and associate with COMPASS- and Polycomb-bound chromatin. Comparing knockout and inducible knockdown systems, we find that acute depletion of DPPA2/4 results in rapid loss of H3K4me3 from key bivalent genes, while H3K27me3 is initially more stable but lost following extended culture. Consequently, upon DPPA2/4 depletion, these promoters gain DNA methylation and are unable to be activated upon differentiation. Our findings uncover a novel epigenetic priming mechanism at developmental promoters, poising them for future lineage-specific activation.

表观遗传景观在发育过程中是如何建立的仍有待阐明。在这里，我们发现发育多能性相关 2 和 4 (DPPA2/4) 作为表观遗传启动因子，在以低表达和稳定的 RNA 聚合酶为特征的发育重要的二价启动子子集中建立了允许的表观遗传景观。分化测定表明， Dppa2/4双敲除小鼠胚胎干细胞无法退出多能性并有效分化。 DPPA2/4 结合 H3K4me3 标记的二价基因启动子，并与 COMPASS 和 Polycomb 结合的染色质结合。比较敲除和诱导敲除系统，我们发现 DPPA2/4 的急性耗竭会导致关键二价基因中的 H3K4me3 快速丢失，而 H3K27me3 最初更稳定，但在扩展培养后丢失。因此，当 DPPA2/4 耗尽时，这些启动子会获得 DNA 甲基化，并且在分化时无法被激活。我们的研究结果揭示了发育启动子的一种新型表观遗传启动机制，为未来的谱系特异性激活做好了准备。