Abstract
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.
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•Mel18 is required for PRC1 stability and maintenance of gene repression in ESCs•Mel18 is essential for ESC differentiation into early cardiac-mesoderm precursors•Different Mel18-PRC1 complexes are assembled during cardiac differentiation•Distinctive PRC1 complexes bind to highly active and repressed genes in MES cells
Morey et al. reveal that Mel18, a Polycomb-complex-associated protein, is an essential epigenetic regulator of cardiac differentiation. During directed differentiation of embryonic stem cells, Morey et al. find that Mel18-PRC1 complexes exchange subunits in a stage-specific manner and instruct sequential gene activation and repression programs to specify mesoderm fate, prevent alternate lineage commitment, and promote cardiac differentiation.
