2. Academic Validation
  3. PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK-ERK signaling

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

  • Nat Genet. 2017 Sep;49(9):1354-1363. doi: 10.1038/ng.3922.
Slim Mzoughi 1 2,  Jingxian Zhang 1,  Delphine Hequet 1,  Shun Xie Teo 1,  Haitong Fang 3,  Qiao Rui Xing 3 4,  Marco Bezzi 1 2,  Michelle Kay Yi Seah 5,  Sheena L M Ong 6,  Eun Myoung Shin 7 8,  Heike Wollmann 9,  Esther S M Wong 6,  Muthafar Al-Haddawi 10,  Colin L Stewart 6,  Vinay Tergaonkar 2 8 11 12,  Yuin-Han Loh 3 13,  N Ray Dunn 6,  Daniel M Messerschmidt 2 5,  Ernesto Guccione 1 2 7 11 14
Affiliations

Affiliations

  • 1 Methyltransferases in Development and Disease Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
  • 2 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 3 Epigenetics and Cell Fates Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
  • 4 School of Biological Sciences, Nanyang Technological University, Singapore.
  • 5 Developmental Epigenetics and Disease Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
  • 6 Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A*STAR), Singapore.
  • 7 Cancer Science Institute of Singapore (CSI), National University of Singapore, Singapore.
  • 8 NF-κB Signaling in Human Ailments, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
  • 9 DNA Sequencing Facility NGS Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
  • 10 Advanced Molecular Pathology Laboratory, IMCB, Singapore.
  • 11 National Cancer Centre Singapore, Singapore.
  • 12 Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
  • 13 Department of Biological Sciences, National University of Singapore, Singapore.
  • 14 Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
PMID: 28740264 DOI: 10.1038/ng.3922
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.

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