Mzoughi, S., Zhang, J., Hequet, D. et al. PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK–ERK signaling. Nat Genet 49, 1354–1363 (2017). https://doi.org/10.1038/ng.3922
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.
We thank F. Aguilo, M. Walsh and W.W. Tee for helpful discussions and critically reading the manuscript, H.-H. Ng (GIS/Singapore) for the kind gift of antibodies, and T. Teng and BRC Shared facilities for technical support. We acknowledge the technical expertise provided by the Advanced Molecular Pathology Laboratory (AMPL) at IMCB, and in particular we thank C.B. Ong. This work was supported by the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore. We acknowledge support from NMRC/OFIRG/0032/2017, an AGA-SINGA (Singapore Graduate Award) fellowship to S.M. and M.B., the French College of Gynecology and Obstetrics to D.H. and an NRF fellowship to D.M.M.
“This is a post-peer-review, pre-copyedit version of an article published in [Nature Genetics]. The final authenticated version is available online at: http://dx.doi.org/10.1038/ng.3922”.