The Polycomb protein Pcgf2/Mel18 regulates mesoderm cell fate-specification of embryonic stem cells through multiple mechanisms

Polycomb complexes are essential regulators of stem cell identity, yet very little is known about their molecular mechanisms during cell differentiation. Pcgf proteins (Pcgf1/2/3/4/5/6) are core subunits of the Polycomb repressive complex 1 (PRC1). It has been recently proposed that specific Pcgf proteins are associated to particular PRC1 complexes, yet the molecular and biological functions of different Pcgf proteins remains largely elusive. Using specific differentiation protocols, we have elucidated a role for Pcgf2/Mel18 in specifically regulating mesoderm differentiation. Mechanistically, during early cardiac mesoderm differentiation, Pcgf2/Mel18 functions as a classical Polycomb protein by repressing pluripotency, lineage specification, late cardiac differentiation and negative regulators of the BMP pathway, yet Pcgf2/Mel18 also positively regulates the expression of key mesoderm transcription factors, revealing a novel function of Pcgf2/Mel18 in gene activation during cardiac differentiation. Mel18 depletion results in an unbalance of pathways that positively and negatively regulate cardiac differentiation. We propose that Mel18 is a novel epigenetic factor that controls mesoderm differentiation by opposing molecular mechanisms.