ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner
ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner
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ADAR1 通过以催化独立的方式调节 microRNA 加工来实现分化和神经诱导
DOI：
10.1038/cr.2015.24
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发表时间：
2015-04-01
期刊：
影响因子：
44.1
通讯作者：
Chen, Ling-Ling
中科院分区：
文献类型：
--
作者：
Chen, Tian;Xiang, Jian-Feng;Chen, Ling-Ling
作用于 RNA 的腺苷脱氨酶 (ADAR) 参与腺苷到肌苷的 RNA 编辑，并与发育和疾病有关。在这里，我们观察到人胚胎干细胞 (hESC) 中 ADAR1 缺陷显着影响 hESC 分化和神经诱导，mRNA 和 miRNA 表达发生广泛变化，包括自我更新相关 miRNA（例如 miR302）的上调。全局编辑分析表明，ADAR1 编辑活性对神经诱导后 ADAR1 缺陷 hESC 中 miRNA/mRNA 表达的改变影响不大。全基因组 iCLIP 研究发现，ADAR1 直接与 pri-miRNA 结合，通过充当 RNA 结合蛋白来干扰 miRNA 的加工。重要的是，在 ADAR1 耗尽的 hESC 神经分化时观察到的 miRNA 和表型的异常表达可以通过酶失活的 ADAR1 突变体来逆转，但不能通过 RNA 结合无效的 ADAR1 突变体来逆转。这些发现表明，ADAR1（而非其编辑活性）通过直接 RNA 相互作用调节 miRNA 生物发生，对 hESC 分化和神经诱导至关重要。
Adenosine deaminases acting on RNA (ADARs) are involved in adenosine-to-inosine RNA editing and are implicated in development and diseases. Here we observed that ADAR1 deficiency in human embryonic stem cells (hESCs) significantly affected hESC differentiation and neural induction with widespread changes in mRNA and miRNA expression, including upregulation of self-renewal-related miRNAs, such as miR302s. Global editing analyses revealed that ADAR1 editing activity contributes little to the altered miRNA/mRNA expression in ADAR1-deficient hESCs upon neural induction. Genome-wide iCLIP studies identified that ADAR1 binds directly to pri-miRNAs to interfere with miRNA processing by acting as an RNA-binding protein. Importantly, aberrant expression of miRNAs and phenotypes observed in ADAR1-depleted hESCs upon neural differentiation could be reversed by an enzymatically inactive ADAR1 mutant, but not by the RNA-binding-null ADAR1 mutant. These findings reveal that ADAR1, but not its editing activity, is critical for hESC differentiation and neural induction by regulating miRNA biogenesis via direct RNA interaction.