DEAD-Box Helicase 18 Counteracts PRC2 to Safeguard Ribosomal DNA in Pluripotency Regulation
DEAD-Box Helicase 18 Counteracts PRC2 to Safeguard Ribosomal DNA in Pluripotency Regulation
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DEAD-Box 解旋酶 18 对抗 PRC2 以保护多能性调控中的核糖体 DNA
DOI：
10.1016/j.celrep.2019.12.021
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发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Shen Xiaohua
中科院分区：
文献类型：
--
作者：
Zhang Hui;Wu Zhongyang;Lu J. Yuyang;Huang Bo;Zhou Hongwei;Xie Wei;Wang Jianlong;Shen Xiaohua
胚胎干细胞（ESCs）具有高水平的核糖体RNA （rRNA）转录和核糖体生物发生。在这里，我们揭示了一个重要的DEAD-box解旋酶DDX18在拮抗多梳抑制复合体2 （PRC2）以阻止抑制H3K27me3标记沉积到多能细胞的rDNA上的意想不到的作用。DDX18在核仁外层结合和隔离PRC2，并在体内和体外抵消PRC2复合物的形成。ddx18敲低导致PRC2和H3K27me3在rDNA位点的占用增加，同时rRNA转录急剧下降，核糖体蛋白表达和翻译减少。生长素诱导的DDX18快速降解增强了PRC2在rDNA上的结合。抑制PRC2部分缓解了ddx18缺失对rRNA转录和ESC自我更新的影响。这些结果表明，DDX18通过对抗表观遗传沉默机制来促进多能性，在保护rDNA的染色质和转录完整性方面发挥了关键作用。
Embryonic stem cells (ESCs) exhibit high levels of ribosomal RNA (rRNA) transcription and ribosome biogenesis. Here, we reveal an unexpected role for an essential DEAD-box helicase, DDX18, in antagonizing the polycomb repressive complex 2 (PRC2) to prevent deposition of the repressive H3K27me3 mark onto rDNA in pluripotent cells. DDX18 binds and sequesters PRC2 in the outer layer of the nucleolus and counteracts PRC2 complex formationin vivoandin vitro.DDX18knockdown leads to increased occupancy of PRC2 and H3K27me3 at rDNA loci, accompanied by drastically decreased rRNA transcription and reduced ribosomal protein expression and translation. Auxin-induced rapid degradation of DDX18 enhances PRC2 binding at rDNA. The inhibition of PRC2 partially rescues the effects ofDDX18depletion on rRNA transcription and ESC self-renewal. These results demonstrate a critical role for DDX18 in safeguarding the chromatin and transcriptional integrity of rDNA by counteracting the epigenetic silencing machinery to promote pluripotency.