eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of stem cell pluripotency.
eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of stem cell pluripotency.
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DOI：
10.1126/sciadv.abm0478
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发表时间：
2022-04
期刊：
影响因子：
13.6
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Li D;Yang J;Huang X;Zhou H;Wang J
翻译控制已经成为蛋白质组复杂性的基本调控层，控制细胞的身份和功能。由于起始是翻译的限速步骤，我们进行了RNA干扰筛选维持胚胎干细胞（ESC）身份所需的关键翻译起始因子。我们确定了真核生物翻译起始因子4A2（eIF4A2），并通过核糖体蛋白S26独立和依赖的核糖体在翻译起始激活编码多能性因子和组蛋白变体H3.3的信使RNA（mRNA）中的作用机制，证实了其在维持干细胞多能性中的作用。eIF4A2还介导Ddx6的翻译起始激活，Ddx6与eIF4A2一起通过Zscan4 mRNA降解和翻译抑制来限制ESC中的全能双细胞转录程序。因此，eIF4A2的敲低破坏ESC蛋白质组，导致ESC身份的丧失。总的来说，我们建立了多能性转录因子和表观遗传调节因子的蛋白质合成的翻译范式，这些转录因子和表观遗传调节因子在控制多能性中的既定作用。eIF4A2介导的翻译控制保障了胚胎干细胞的身份。
Translational control has emerged as a fundamental regulatory layer of proteome complexity that governs cellular identity and functions. As initiation is the rate-limiting step of translation, we carried out an RNA interference screen for key translation initiation factors required to maintain embryonic stem cell (ESC) identity. We identified eukaryotic translation initiation factor 4A2 (eIF4A2) and defined its mechanistic action through ribosomal protein S26–independent and –dependent ribosomes in translation initiation activation of messenger RNAs (mRNAs) encoding pluripotency factors and the histone variant H3.3 with demonstrated roles in maintaining stem cell pluripotency. eIF4A2 also mediates translation initiation activation of Ddx6, which acts together with eIF4A2 to restrict the totipotent two-cell transcription program in ESCs through Zscan4 mRNA degradation and translation repression. Accordingly, knockdown of eIF4A2 disrupts ESC proteome, causing the loss of ESC identity. Collectively, we establish a translational paradigm of the protein synthesis of pluripotency transcription factors and epigenetic regulators imposed on their established roles in controlling pluripotency. eIF4A2-mediated translational control safeguards embryonic stem cell identity.
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影响因子：
64.5
作者：
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