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. Epub 2017 Jul 24.


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.

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Self Renewal / genetics
  • Cells, Cultured
  • Cellular Reprogramming / genetics
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Embryonic Stem Cells / metabolism*
  • Fluorescent Antibody Technique
  • Gene Expression Profiling / methods
  • Gene Expression Regulation*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • MAP Kinase Signaling System / genetics*
  • Mice, Knockout
  • Mice, Nude
  • Mice, Transgenic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Wnt Signaling Pathway / genetics*


  • DNA-Binding Proteins
  • PRDM15 protein, human
  • PRDM15 protein, mouse
  • Transcription Factors