SETDB1 is essential for mouse primordial germ cell fate determination by ensuring BMP signaling
SETDB1 is essential for mouse primordial germ cell fate determination by ensuring BMP signaling
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DOI：
10.1242/dev.164160
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发表时间：
2018-12-01
期刊：
影响因子：
4.6
通讯作者：
Matsui, Yasuhisa
中科院分区：
文献类型：
--
作者：
Mochizuki, Kentaro;Tandot, Yukiko;Matsui, Yasuhisa
在小鼠胚胎中，原始生殖细胞（PGCs）由上胚层细胞决定命运。参与PGC形成的信号通路已被确定，但其表观遗传机制仍知之甚少。在这里，我们表明，组蛋白甲基转移酶SETDB 1是PGC命运决定的表观遗传调节。Setdb/-缺陷胚胎表现出新生PGCs的急剧减少。Dppa 2，Otx 2和Ulf 1被去抑制，而中胚层发育相关基因，包括BMP 4信号相关基因，在PGCLC诱导过程中被Setdb 1敲低下调。此外，在含有PGCLC的细胞聚集体中，在Dppa 2、Otx 2和UTF 1的侧翼区域观察到SETDB 1的结合，并且在这些区域通过Setdb 1敲低降低组蛋白H3的赖氨酸9的三甲基化。此外，DPPA 2、OTX 2和UTF 1结合在编码BMP 4信号相关蛋白（包括SMAD 1）的基因中增加。最后，在含有PGCLC的细胞聚集体中Dppa 2、Otx 2和Utf 1的过表达导致BMP 4信号相关基因和PGC决定子基因的抑制。我们认为SETDB 1定位于Dppa 2、Otx 2和Utf 1，并随后抑制它们的表达，通过确保BMP 4信号传导对PGC测定至关重要。
In mouse embryos, primordial germ cells (PGCs) are fate-determined from epiblast cells. Signaling pathways involved in PGC formation have been identified, but their epigenetic mechanisms remain poorly understood. Here, we show that the histone methyltransferase SETDB1 is an epigenetic regulator of PGC fate determination. Setdb/-deficient embryos exhibit drastic reduction of nascent PGCs. Dppa2, Otx2 and Ulf1 are de-repressed whereas mesoderm development-related genes, including BMP4 signaling-related genes, are downregulated by Setdb1 knockdown during PGC-like cell (PGCLC) induction. In addition, binding of SETDB1 is observed at the flanking regions of Dppa2, Otx2 and UTF1 in cell aggregates containing PGCLCs, and trimethylation of lysine 9 of histone H3 is reduced by Setdb1 knockdown at those regions. Furthermore, DPPA2, OTX2 and UTF1 binding is increased in genes encoding BMP4 signaling-related proteins, including SMAD1. Finally, overexpression of Dppa2, Otx2 and Utf1 in cell aggregates containing PGCLCs results in the repression of BMP4 signaling-related genes and PGC determinant genes. We propose that the localization of SETDB1 to Dppa2, Otx2 and Utf1, and subsequent repression of their expression, are crucial for PGC determination by ensuring BMP4 signaling.