Polycomb Regulates Mesoderm Cell Fate-Specification in Embryonic Stem Cells through Activation and Repression Mechanisms
Polycomb Regulates Mesoderm Cell Fate-Specification in Embryonic Stem Cells through Activation and Repression Mechanisms
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DOI：
10.1016/j.stem.2015.08.009
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发表时间：
2015-09-01
期刊：
影响因子：
23.9
通讯作者：
Di Croce, Luciano
中科院分区：
文献类型：
--
作者：
Morey, Lluis;Santanach, Alexandra;Di Croce, Luciano
多梳复合物（PRC1和PRC2）是胚胎和成体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过程，但鲜为人知的是如何组成不同的Polycomb复合物指导和维持细胞命运的机制基础。在这里，我们发现，梅尔18，也被称为Pcgf 2和六个Pcgf旁系同源之一，独特地调节PRC1指定胚胎干细胞中胚层细胞的命运。从机制上讲，Mel18在早期心脏中胚层分化过程中通过抑制多能性、谱系特化、晚期心脏分化和BMP途径的负调节物而作为经典的Polycomb蛋白发挥作用。然而，Mel 18还积极调节关键中胚层转录因子的表达，揭示了Mel 18在心脏分化期间基因激活中意想不到的功能。综上所述，我们的研究结果表明，Mel18需要指定PRC1功能的上下文和阶段特定的方式。
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.