Polycomb Regulates Mesoderm Cell Fate-Specification in Embryonic Stem Cells through Activation and Repression Mechanisms

Cell Stem Cell. 2015 Sep 3;17(3):300-15. doi: 10.1016/j.stem.2015.08.009.


Polycomb complexes (PRC1 and PRC2) are essential regulators of epigenetic gene silencing in embryonic and adult stem cells. Emerging evidence suggests that the core subunit composition regulates distinct biological processes, yet little is known about the mechanistic underpinnings of how differently composed Polycomb complexes instruct and maintain cell fate. Here we find that Mel18, also known as Pcgf2 and one of six Pcgf paralogs, uniquely regulates PRC1 to specify mesoderm cell fate in embryonic stem cells. Mechanistically, Mel18 functions as a classical Polycomb protein during early cardiac mesoderm differentiation by repressing pluripotency, lineage specification, late cardiac differentiation, and negative regulators of the BMP pathway. However, Mel18 also positively regulates expression of key mesoderm transcription factors, revealing an unexpected function of Mel18 in gene activation during cardiac differentiation. Taken together, our findings reveal that Mel18 is required to specify PRC1 function in both a context- and stage-specific manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism
  • Cartilage / cytology
  • Cell Differentiation
  • Cell Lineage*
  • Embryoid Bodies / cytology
  • Gene Expression Regulation*
  • Genome
  • Mesoderm / cytology*
  • Mice
  • Mouse Embryonic Stem Cells / cytology*
  • Mouse Embryonic Stem Cells / metabolism
  • Myocardium / cytology
  • Myocytes, Cardiac / cytology
  • Polycomb Repressive Complex 1 / deficiency
  • Polycomb Repressive Complex 1 / metabolism
  • Polycomb-Group Proteins / metabolism*
  • Protein Binding
  • Protein Stability
  • Signal Transduction
  • Transcription, Genetic


  • Bone Morphogenetic Proteins
  • Pcgf6 protein, mouse
  • Polycomb-Group Proteins
  • Polycomb Repressive Complex 1

Associated data

  • GEO/GSE67868