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  current news   Press   selected story    
     
  31 July 2017  
 
PRDM15 safeguards naïve pluripotency by transcriptionally regulating WNT and MAPK/ERK signalling
 
 




Authors
Slim Mzoughi1,2, Jingxian Zhang1, Delphine Hequet1, Shun Xie Teo1, Haitong Fang3, Qiao Rui Xing3,4, Marco Bezzi1,2, Michelle Kay Yi Seah5, Sheena L.M. Ong6, Eun Myoung Shin7,8, Heike Wollmann9, Esther S.M. Wong6, Muthafar Al-Haddawi10, Colin L. Stewart6, Vinay Tergaonkar2,8,11,12, Yuin-Han Loh3,13, N. Ray Dunn6, Daniel M. Messerschmidt2,5 and Ernesto Guccione1,2,7,11,14*

1  Methyltransferases in Development and Disease Group, Institute of Molecular and Cell Biology, Agency    for Science, Technology and Research (A*STAR), Singapore 138673, Singapore
2  Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8    Medical Drive, Singapore 117597, Singapore.
3  Epigenetics and Cell Fates Group, Institute of Molecular and Cell Biology, Agency for Science,    Technology and Research (A*STAR), Singapore 138673, Singapore
4  School of Biological Sciences, Nanyang Technological University, 637551, Singapore
5  Developmental Epigenetics and Disease Group, Institute of Molecular and Cell Biology, Agency for    Science, Technology and Research (A*STAR), Singapore 138673, Singapore
6  Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A*STAR), 138648,    Singapore.
7  Cancer Science Institute of Singapore (CSI), National University of Singapore, 14 Medical Drive,    Singapore 117599, Singapore
8  NFκB Signaling in Human Ailments, Institute of Molecular and Cell Biology, Agency for Science,    Technology and Research (A*STAR), Singapore 138673, Singapore
9  DNA Sequencing Facility NGS unit, Institute of Molecular and Cell Biology, Agency for Science,    Technology and Research (A*STAR), Singapore 138673, Singapore
10 Advanced Molecular Pathology Laboratory, IMCB, Singapore
11 National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
12 Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide SA 5000, Australia
13 Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
14 Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York

*Correspondence: Ernesto Guccione, eguccione@imcb.a-star.edu.sg

Published online in Nature Genetics on 24 July 2017.

Abstract
The transcriptional network acting downstream of LIF, WNT and MAPK/ERK to stabilize mouse embryonic stem cells (ESCs) in their ground state has been extensively characterized. However, the upstream factors regulating these three main signaling pathways remain uncharted.
PR domain-containing proteins (PRDM) are Zn-fingers sequence-specific chromatin factors that play essential roles in embryonic development and cell fate decisions.

Here, we characterize PRDM15, a transcription regulator, which acts independently from PRDM14, to regulate the mouse naïve ESC state. Mechanistically, PRDM15 modulates WNT- and MAPK/ERK-signaling by directly promoting the expression of R-spondin1 (Rspo1) and Sprouty1 (Spry1). Consistently, CRISPR-mediated disruption of PRDM15 binding sites at the Rspo1 and Spry1 promoters, recapitulates PRDM15 depletion both in terms of local chromatin organization and of their transcriptional modulation.

Collectively, our findings uncover an essential role of PRDM15 as a chromatin factor which modulates the transcription of upstream regulators of WNT and MAPK/ERK signaling to safeguard naïve pluripotency.

Figure

Figure legend

Proposed model for PRDM15 activity in ESCs. PRDM15 regulates Spry1 and Rspo1 transcription through recognition and direct binding of a specific DNA sequence in their promoter regions. Activation of Spry1 and Rspo1 expression leads to inhibition of the ERK–MAPK pathway and activation of the WNT–β-catenin pathway, respectively.
Maintaining this balance shields ESCs from external differentiation cues and ensures their self-renewal in a naive state.

For more information on Ernesto GUCCIONE's lab, please click here.