The G4 resolvase RHAU regulates ventricular trabeculation and compaction through transcriptional and post-transcriptional mechanisms.
The G4 resolvase RHAU regulates ventricular trabeculation and compaction through transcriptional and post-transcriptional mechanisms.
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G4 解离酶 RHAU 通过转录和转录后机制调节心室小梁形成和压缩。
DOI：
10.1016/j.jbc.2021.101449
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Huang X;Zhao K;Jiang M;Qiu D;Zhou J;Yang Z
富含AU元件的G-四链体（G4）解离酶RNA解旋酶（RHAU）具有解旋DNA和RNA分子中G4结构的能力。以前，我们发现RHAU通过调节mRNA翻译和稳定性在胚胎心脏发育和出生后心脏功能中起着关键作用。然而，是否RHAU功能，以解决DNA G4在心脏生理的调节仍然是难以捉摸的。在此，我们在心肌细胞特异性Rhau缺失小鼠中鉴定了致密化不全心肌病的表型，包括海绵状心肌病、心脏扩张和幼年死亡等症状。我们还观察到Rhau突变小鼠心肌细胞增殖减少和肌节成熟提前。进一步的研究表明，RHAU调节与心室小梁形成和致密化相关的几种基因的表达水平，包括编码心脏转录因子NKX 2 - 5和Hey 2的Nkx 2 - 5和Hey 2，以及蛋白产物为MYH 7的肌球蛋白重链7（Myh 7）。虽然RHAU在转录后水平调节Nkx 2 -5 mRNA和Hey 2 mRNA，但我们发现RHAU通过解旋其启动子中的G4结构来促进Myh 7的转录。这些结果表明，RHAU调控心室腔发育通过转录和转录后机制。这些结果有助于知识基础，将有助于了解疾病的发病机制，如致密化不全心肌病。
The G-quadruplex (G4) resolvase RNA helicase associated with AU-rich element (RHAU) possesses the ability to unwind G4 structures in both DNA and RNA molecules. Previously, we revealed that RHAU plays a critical role in embryonic heart development and postnatal heart function through modulating mRNA translation and stability. However, whether RHAU functions to resolve DNA G4 in the regulation of cardiac physiology is still elusive. Here, we identified a phenotype of noncompaction cardiomyopathy in cardiomyocyte-specific Rhau deletion mice, including such symptoms as spongiform cardiomyopathy, heart dilation, and death at young ages. We also observed reduced cardiomyocyte proliferation and advanced sarcomere maturation in Rhau mutant mice. Further studies demonstrated that RHAU regulates the expression levels of several genes associated with ventricular trabeculation and compaction, including the Nkx2-5 and Hey2 that encode cardiac transcription factors of NKX2-5 and Hey2, and the myosin heavy chain 7 (Myh7) whose protein product is MYH7. While RHAU modulates Nkx2-5 mRNA and Hey2 mRNA at the post-transcriptional level, we uncovered that RHAU facilitates the transcription of Myh7 through unwinding of the G4 structures in its promoter. These findings demonstrated that RHAU regulates ventricular chamber development through both transcriptional and post-transcriptional mechanisms. These results contribute to a knowledge base that will help to understand the pathogenesis of diseases such as noncompaction cardiomyopathy.
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影响因子：
16.6
作者：
Tian X;Li Y;He L;Zhang H;Huang X;Liu Q;Pu W;Zhang L;Li Y;Zhao H;Wang Z;Zhu J;Nie Y;Hu S;Sedmera D;Zhong TP;Yu Y;Zhang L;Yan Y;Qiao Z;Wang QD;Wu SM;Pu WT;Anderson RH;Zhou B
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