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.
Centre for Genomic Regulation (CRG), Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
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.
多梳复合物（PRC1 和 PRC2）是胚胎和成年干细胞中表观遗传基因沉默的重要调节因子。新出现的证据表明，核心亚基组成调节不同的生物学过程，但对于不同组成的多梳复合物如何指导和维持细胞命运的机制基础知之甚少。在这里，我们发现 Mel18，也称为 Pcgf2，是六个 Pcgf 同源物之一，它独特地调节 PRC1 以在胚胎干细胞中指定中胚层细胞命运。在机制上，Mel18 在早期心脏中胚层分化过程中作为一种经典的多梳蛋白发挥作用，通过抑制多能性、谱系特化、晚期心脏分化以及 BMP 途径的负调节剂来发挥作用。然而，Mel18 也正向调节关键中胚层转录因子的表达，揭示了 Mel18 在心脏分化过程中基因激活中的一个意外功能。总之，我们的研究结果表明，Mel18 以特定于上下文和阶段的方式来指定 PRC1 功能。
