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

Ernesto Guccione and colleagues report that the transcription factor PRDM15 regulates naive pluripotency in mouse embryos and embryonic stem cells and in derivation of mouse and human iPSCs. They further show that PRDM15 promotes WNT signaling and inhibits MAPK–ERK signaling by directly regulating t...

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Published in:	Nature genetics Vol. 49; no. 9; pp. 1354 - 1363
Main Authors:	Mzoughi, Slim, Zhang, Jingxian, Hequet, Delphine, Teo, Shun Xie, Fang, Haitong, Xing, Qiao Rui, Bezzi, Marco, Seah, Michelle Kay Yi, Ong, Sheena L M, Shin, Eun Myoung, Wollmann, Heike, Wong, Esther S M, Al-Haddawi, Muthafar, Stewart, Colin L, Tergaonkar, Vinay, Loh, Yuin-Han, Dunn, N Ray, Messerschmidt, Daniel M, Guccione, Ernesto
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-09-2017 Nature Publishing Group
Subjects:	13/1 13/100 13/106 14/63 38/39 45/91 631/208/177 631/337/176 631/532 64/60 Agriculture Animal Genetics and Genomics Animals Binding sites Biomedicine Blotting, Western Cancer Research Cell fate Cell Line Cell Self Renewal - genetics Cells, Cultured Cellular Reprogramming - genetics Cellular signal transduction Chromatin CRISPR DNA methylation DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Embryo cells Embryogenesis Embryonic development Embryonic growth stage Embryonic stem cells Embryonic Stem Cells - metabolism Extracellular signal-regulated kinase Fluorescent Antibody Technique Gene Expression Profiling - methods Gene Expression Regulation Gene Function Genetic aspects Human Genetics Humans Induced Pluripotent Stem Cells - metabolism Kinases MAP kinase MAP Kinase Signaling System - genetics Mice, Knockout Mice, Nude Mice, Transgenic Physiological aspects Pluripotency Promoters Proteins Regulators Reverse Transcriptase Polymerase Chain Reaction Rodents Stem cell transplantation Stem cells Transcription Factors - genetics Transcription Factors - metabolism Wnt protein Wnt Signaling Pathway - genetics Zinc finger proteins United States Singapore
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Summary:	Ernesto Guccione and colleagues report that the transcription factor PRDM15 regulates naive pluripotency in mouse embryos and embryonic stem cells and in derivation of mouse and human iPSCs. They further show that PRDM15 promotes WNT signaling and inhibits MAPK–ERK signaling by directly regulating the expression of R-spondin1 and Sprouty1, respectively. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1061-4036 1546-1718
DOI:	10.1038/ng.3922