Polycomb Regulates Mesoderm Cell Fate-Specification in Embryonic Stem Cells through Activation and Repression Mechanisms.
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.
Centre for Genomic Regulation (CRG), Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: lmorey@med.miami.edu.
Lluis
L
Morey
Centre for Genomic Regulation (CRG), Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Alexandra
A
Santanach
Centre for Genomic Regulation (CRG), Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Enrique
E
Blanco
Centre for Genomic Regulation (CRG), Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Luigi
L
Aloia
Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Department of Pediatrics, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA 94158, USA.
Elphège P
EP
Nora
Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Department of Pediatrics, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA 94158, USA.
Benoit G
BG
Bruneau
Centre for Genomic Regulation (CRG), Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Passeig Lluis Companys 23, 08010 Barcelona, Spain. Electronic address: luciano.dicroce@crg.eu.
Luciano
L
Di Croce
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002356:Cartilage / Q000166:cytology; D002454:Cell Differentiation; D019070:Cell Lineage; D058732:Embryoid Bodies / Q000166:cytology; D005786:Gene Expression Regulation; D016678:Genome; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology; D063150:Polycomb Repressive Complex 1 / Q000172:deficiency / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D015398:Signal Transduction; D014158:Transcription, Genetic
D019485:Bone Morphogenetic Proteins; C066476:Pcgf6 protein, mouse; D063146:Polycomb-Group Proteins; D063150:Polycomb Repressive Complex 1