The transcriptional network acting downstream of LIF, WNT and MAPK-ERK to stabilize mouse embryonic stem cells (ESCs) in their naive state has been extensively characterized. However, the upstream factors regulating these three signaling pathways remain largely uncharted. PR-domain-containing proteins (PRDMs) are zinc-finger sequence-specific chromatin factors that have essential roles in embryonic development and cell fate decisions. Here we characterize the transcriptional regulator PRDM15, which acts independently of PRDM14 to regulate the naive state of mouse ESCs. Mechanistically, PRDM15 modulates WNT and MAPK-ERK signaling by directly promoting the expression of Rspo1 (R-spondin1) and Spry1 (Sprouty1). Consistent with these findings, CRISPR-Cas9-mediated disruption of PRDM15-binding sites in the Rspo1 and Spry1 promoters recapitulates PRDM15 depletion, both in terms of local chromatin organization and the transcriptional modulation of these genes. Collectively, our findings uncover an essential role for PRDM15 as a chromatin factor that modulates the transcription of upstream regulators of WNT and MAPK-ERK signaling to safeguard naive pluripotency.

中文翻译：

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PRDM15通过转录调控WNT和MAPK-ERK信号传导来保护幼稚的多能性。

在LIF，WNT和MAPK-ERK下游起作用以稳定小鼠幼稚干细胞（ESCs）处于幼稚状态的转录网络已得到广泛表征。但是，调节这三个信号通路的上游因素仍然未知。含PR结构域的蛋白（PRDM）是锌指序列特异的染色质因子，在胚胎发育和细胞命运决定中具有重要作用。在这里，我们表征了转录调节因子PRDM15，其独立于PRDM14发挥作用来调节小鼠ESC的幼稚状态。机械上，PRDM15通过直接促进Rspo1（R-spondin1）和Spry1（Sprouty1）的表达来调节WNT和MAPK-ERK信号传导。与这些发现一致，CRISPR-Cas9介导的Rspo1和Spry1启动子中PRDM15结合位点的破坏从局部染色质组织和这些基因的转录调节方面概括了PRDM15的消耗。总的来说，我们的发现揭示了PRDM15作为染色质因子的重要作用，它可以调节WNT和MAPK-ERK信号上游调节因子的转录，从而保护幼稚的多能性。