PRDM15 Safeguards Naive Pluripotency by Transcriptionally Regulating WNT and MAPK-ERK Signaling

Overview

Journal Nat Genet

Specialty Genetics

Date 2017 Jul 26

PMID 28740264

Citations 29

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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