Pramel7 mediates ground-state pluripotency through proteasomal-epigenetic combined pathways

Nat Cell Biol. 2017 Jul;19(7):763-773. doi: 10.1038/ncb3554. Epub 2017 Jun 12.


Naive pluripotency is established in preimplantation epiblast. Embryonic stem cells (ESCs) represent the immortalization of naive pluripotency. 2i culture has optimized this state, leading to a gene signature and DNA hypomethylation closely comparable to preimplantation epiblast, the developmental ground state. Here we show that Pramel7 (PRAME-like 7), a protein highly expressed in the inner cell mass (ICM) but expressed at low levels in ESCs, targets for proteasomal degradation UHRF1, a key factor for DNA methylation maintenance. Increasing Pramel7 expression in serum-cultured ESCs promotes a preimplantation epiblast-like gene signature, reduces UHRF1 levels and causes global DNA hypomethylation. Pramel7 is required for blastocyst formation and its forced expression locks ESCs in pluripotency. Pramel7/UHRF1 expression is mutually exclusive in ICMs whereas Pramel7-knockout embryos express high levels of UHRF1. Our data reveal an as-yet-unappreciated dynamic nature of DNA methylation through proteasome pathways and offer insights that might help to improve ESC culture to reproduce in vitro the in vivo ground-state pluripotency.

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism*
  • Blastocyst / cytology
  • Blastocyst / enzymology*
  • CCAAT-Enhancer-Binding Proteins
  • Cullin Proteins / metabolism
  • DNA Methylation
  • Embryonic Stem Cells / enzymology*
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Humans
  • Mice, Inbred C57BL
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phenotype
  • Pluripotent Stem Cells / enzymology*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Interaction Domains and Motifs
  • Protein Stability
  • Proteolysis
  • RNA Interference
  • Time Factors
  • Transcriptome
  • Transfection
  • Ubiquitin-Protein Ligases


  • Antigens, Neoplasm
  • CCAAT-Enhancer-Binding Proteins
  • CUL2 protein, human
  • Cullin Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • Pramel7 protein, mouse
  • Ubiquitin-Protein Ligases
  • Uhrf1 protein, mouse
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease