RNA G-quadruplex Regulates MicroRNA-26a Biogenesis and Function,Journal of Hepatology

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RNA G-quadruplex Regulates MicroRNA-26a Biogenesis and Function
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-08-01 , DOI: 10.1016/j.jhep.2020.02.032
Geng Liu ₁ , Wenya Du ₁ , Haixia Xu ₁ , Qiu Sun ₂ , Dongmei Tang ₁ , Sailan Zou ₁ , Yu Zhang ₁ , Meilin Ma ₁ , Guixiang Zhang ₃ , Xiao Du ₄ , Shenggen Ju ₅ , Wei Cheng ₂ , Yan Tian ₁ , Xianghui Fu ₁

Affiliation

BACKGROUND & AIMS RNA G-quadruplexes (RG4s) appear to be important in post-transcriptional gene regulation, but their pathophysiological functions remain unknown. MicroRNA-26a (miR-26a) is emerging as a therapeutic target for various human diseases, however the mechanisms underlying endogenous miR-26a regulation are poorly understood. Here we report a role of RG4 in miR-26a expression and function in vitro and in vivo. METHODS Putative RG4s within liver-enriched miRNAs were predicted by bioinformatical analysis, and the presence of RG4 structure in miR-26a-1 precursor (pre-miR-26a-1) was further analyzed by biophysical and biochemical methods. RG4 stabilizers, pre-miR-26a-1 overexpression plasmids, and luciferase reporter assay were used to assess the effect of RG4 on pre-miR-26a-1 maturation. Both miR-26a knockin and knockout mouse models were employed to investigate the influence of this RG4 on miR-26a expression and function. Moreover, the interaction between RG4 in pre-miR-26a-1 and DEAH-box helicase 36 (DHX36) was determined by biophysical and molecular methods. Finally, the miR-26a processing and DHX36 expression were quantified in the livers from genetic and diet-induced obese mouse models. RESULTS We identify a guanine-rich sequence in pre-miR-26a-1 that can fold into RG4 structure. This RG4 impairs pre-miR-26a-1 maturation, resulting in a decrease in miR-26a expression and subsequently an increase in miR-26a cognate targets. In line with known miR-26a function, this RG4 can regulate hepatic insulin sensitivity and lipid metabolism in vitro and in vivo. Furthermore, we reveal that DHX36 can bind and unwind this RG4 structure, thereby enhancing miR-26a maturation. Intriguingly, there is a concordant decrease of miR-26a maturation and DHX36 expression in obese mouse livers. CONCLUSIONS Our findings define a dynamic DHX36/RG4/miR-26a regulatory axis during obesity, highlighting an important role of RG4 in physiology and pathology.

中文翻译：

RNA G-四链体调节 MicroRNA-26a 生物发生和功能

背景和目的 RNA G-四链体 (RG4s) 似乎在转录后基因调控中很重要，但它们的病理生理学功能仍然未知。MicroRNA-26a (miR-26a) 正在成为各种人类疾病的治疗靶点，但对内源性 miR-26a 调控的机制知之甚少。在这里，我们报告了 RG4 在 miR-26a 表达和体外和体内功能中的作用。方法通过生物信息学分析预测富含肝脏的 miRNA 中推定的 RG4，并通过生物物理和生化方法进一步分析 miR-26a-1 前体（pre-miR-26a-1）中 RG4 结构的存在。RG4 稳定剂、pre-miR-26a-1 过表达质粒和荧光素酶报告基因检测用于评估 RG4 对 pre-miR-26a-1 成熟的影响。使用 miR-26a 敲入和敲除小鼠模型来研究该 RG4 对 miR-26a 表达和功能的影响。此外，通过生物物理和分子方法确定了 pre-miR-26a-1 中的 RG4 与 DEAH-box 解旋酶 36 (DHX36) 之间的相互作用。最后，在来自遗传和饮食诱导的肥胖小鼠模型的肝脏中量化了 miR-26a 加工和 DHX36 表达。结果我们在 pre-miR-26a-1 中鉴定了一个富含鸟嘌呤的序列，它可以折叠成 RG4 结构。该 RG4 会损害 pre-miR-26a-1 的成熟，导致 miR-26a 表达降低，随后 miR-26a 同源靶标增加。与已知的 miR-26a 功能一致，这种 RG4 可以在体外和体内调节肝脏胰岛素敏感性和脂质代谢。此外，我们揭示了 DHX36 可以结合和解开这种 RG4 结构，从而促进 miR-26a 的成熟。有趣的是，肥胖小鼠肝脏中 miR-26a 成熟和 DHX36 表达一致降低。结论我们的研究结果定义了肥胖期间的动态 DHX36/RG4/miR-26a 调节轴，突出了 RG4 在生理学和病理学中的重要作用。

更新日期：2020-08-01

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