Methyltransferases in Development and Disease Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Nat Genet. 2017 Sep;49(9):1354-1363. doi: 10.1038/ng.3922. Epub 2017 Jul 24.
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.
下游转录网络作用于 LIF、WNT 和 MAPK-ERK，以稳定其幼稚状态的小鼠胚胎干细胞（ESC），该网络已被广泛研究。然而，调节这三个信号通路的上游因素在很大程度上仍未被发现。PR 结构域包含蛋白（PRDMs）是锌指序列特异性染色质因子，在胚胎发育和细胞命运决定中具有重要作用。本文我们对转录调控因子 PRDM15 进行了研究，该因子独立于 PRDM14 发挥作用，可调节小鼠 ESC 的幼稚状态。从机制上讲，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。这些发现表明，CRISPR-Cas9 介导的 PRDM15 结合位点在 Rspo1 和 Spry1 启动子上的破坏，在局部染色质组织和这些基因的转录调节方面，均能重现 PRDM15 的耗竭。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，它调节 WNT 和 MAPK-ERK 信号上游调节因子的转录，以维持幼稚多能性。
