PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling

Slim Mzoughi, Jingxian Zhang, Delphine Hequet, Shun Xie Teo, Haitong Fang, Qiao Rui Xing, Marco Bezzi, Michelle Kay Yi Seah, Sheena L.M. Ong, Eun Myoung Shin, Heike Wollmann, Esther S.M. Wong, Muthafar Al-Haddawi, Colin L. Stewart, Vinay Tergaonkar, Yuin Han Loh, N. Ray Dunn, Daniel M. Messerschmidt, Ernesto Guccione

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1354-1363
Number of pages10
JournalNature Genetics
Volume49
Issue number9
DOIs
StatePublished - 1 Sep 2017

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