The messenger RNA (mRNA) 3' untranslated regions (3' UTRs), as cis-regulated elements bound by microRNAs (miRNAs), affect their gene translation. However, the role of the trans-regulation of 3' UTRs during heart dysfunction remains elusive. Compared with administration of angiogenic factor with G-patch and forkhead-associate domains 1 (Aggf1), ectopic expression of Aggf1 with its 3' UTR significantly suppressed cardiac dysfunction in angiotensin II-infused mice, with upregulated expression of both Aggf1 and myeloid cell leukemia 1 (Mcl1). Along their 3' UTRs, Mcl1 and Aggf1 mRNAs share binding sites for the same miRNAs, including miR-105, miR-101, and miR-93. We demonstrated that the protein-coding Mcl1 and Aggf1 mRNAs communicate and co-regulate each other's expression through competition for these three miRNAs that target both transcripts via their 3' UTRs. Our results indicate that Aggf1 3' UTR, as a trans-regulatory element, accelerates the cardioprotective role of Aggf1 in response to hypertensive conditions by elevating Mcl1 expression. Our work broadens the scope of gene therapy targets and provides a new insight into gene therapy strategies involving 3' UTRs.

中文翻译：

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3'非翻译区通过AGGF1表达保护心脏免受血管紧张素II引起的心脏功能障碍。

信使RNA（mRNA）3'非翻译区（3'UTR）作为由microRNA（miRNA）结合的顺式调控元件，影响其基因翻译。但是，在心脏功能障碍期间3'UTRs的反式调节作用仍然不清楚。与具有G斑块和叉头相关结构域1（Aggf1）的血管生成因子相比，异位表达Aggf1及其3'UTR显着抑制了注入血管紧张素II的小鼠的心脏功能障碍，同时上调了Aggf1和髓样细胞白血病的表达1（Mcl1）。沿着其3'UTR，Mcl1和Aggf1 mRNA共享相同miRNA的结合位点，包括miR-105，miR-101和miR-93。我们证明了编码蛋白质的Mcl1和Aggf1 mRNA相互沟通和共同调节。通过竞争通过这两个miRNA的3'UTR靶向这两个转录本的miRNA的表达。我们的结果表明，Aggf1 3'UTR作为一种反式调节元件，通过升高Mcl1表达来加速Aggf1对高血压病的心脏保护作用。我们的工作拓宽了基因治疗目标的范围，并为涉及3'UTR的基因治疗策略提供了新的见解。