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中外科学家合作揭示胚胎发育过程中全局miRNA的剂量控制
2021-05-06 14:09

美国波士顿儿童医院Richard I. Gregory和北京大学杜鹏组合作的最新研究提出了胚胎胚层特异性全局小RNA(miRNA)剂量控制。这一研究成果于2021年5月5日在线发表在国际学术期刊《自然》上。

在本研究中,研究人员介绍了发育过程中miRNA剂量的控制机制,涉及DGCR8的替代转录起始(ATI)。ATI发生在DGCR8 mRNA的茎环下游,绕过小鼠胚胎干细胞(mES)分化过程的自调节反馈环路。敲除茎环会导致DGCR8:DROSHA蛋白化学计量失衡,从而导致不可逆的 Microprocessor聚集,初级miRNA加工减少、成熟miRNA丰度降低以及与脂质代谢相关mRNA的广泛抑制。

尽管全局miRNA剂量控制对于mES细胞多能性丧失非必需,但其失调会通过破坏体外和体内胚层发育来改变脂质代谢途径并干扰胚胎发育。这种miRNA剂量控制机制在人类中也是保守的。该研究结果发现了一个启动子开关,该开关可以平衡 Microprocessor的自动调节和聚集,以精确控制全局miRNA剂量并在早期胚胎发育过程中控制干细胞的命运决定。

据悉,miRNA在胚胎发育过程中发挥重要功能,其失调会引发癌症。在不同的组织和肿瘤中发现了全局miRNA丰度的改变,这意味着精准调控miRNA的剂量至关重要,但是这种调控的潜在机制仍然未知。由DROSHA和两分子DGCR8蛋白组成的蛋白质复合物 Microprocessor对于miRNA的生物发生必不可少。

附:英文原文

Title: Global miRNA dosage control of embryonic germ layer specification

Author: Yingzi Cui, Xuehui Lyu, Li Ding, Lan Ke, Dechang Yang, Mehdi Pirouz, Ye Qi, Jennie Ong, Ge Gao, Peng Du, Richard I. Gregory

Issue&Volume: 2021-05-05

Abstract: MicroRNAs (miRNAs) have essential functions during embryonic development, and their dysregulation causes cancer1,2. Altered global miRNA abundance is found in different tissues and tumours, which implies that precise control of miRNA dosage is important1,3,4, but the underlying mechanism(s) of this control remain unknown. The protein complex Microprocessor, which comprises one DROSHA and two DGCR8 proteins, is essential for miRNA biogenesis5,6,7. Here we identify a developmentally regulated miRNA dosage control mechanism that involves alternative transcription initiation (ATI) of DGCR8. ATI occurs downstream of a stem-loop in DGCR8 mRNA to bypass an autoregulatory feedback loop during mouse embryonic stem (mES) cell differentiation. Deletion of the stem-loop causes imbalanced DGCR8:DROSHA protein stoichiometry that drives irreversible Microprocessor aggregation, reduced primary miRNA processing, decreased mature miRNA abundance, and widespread de-repression of lipid metabolic mRNA targets. Although global miRNA dosage control is not essential for mES cells to exit from pluripotency, its dysregulation alters lipid metabolic pathways and interferes with embryonic development by disrupting germ layer specification in vitro and in vivo. This miRNA dosage control mechanism is conserved in humans. Our results identify a promoter switch that balances Microprocessor autoregulation and aggregation to precisely control global miRNA dosage and govern stem cell fate decisions during early embryonic development.

DOI: 10.1038/s41586-021-03524-0

Source: https://www.nature.com/articles/s41586-021-03524-0

 

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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