A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling

压力过载 基因亚型 转基因小鼠 环状RNA RNA剪接 骨膜炎 转基因 心室重构 纤维化 选择性拼接 核糖核酸 RNA结合蛋白 基因沉默 心力衰竭 生物 细胞生物学 内科学 医学 遗传学 基因 细胞外基质 心肌肥大
作者
William W. Du,Jindong Xu,Weining Yang,Nan Wu,Feiya Li,Le Zhou,Sheng Wang,Xiangmin Li,Alina T. He,Kevin Y. Du,Kaixuan Zeng,Jian Ma,Juanjuan Lyu,Chao Zhang,Chi Zhou,Katarina Maksimovic,Burton B. Yang
出处
期刊:Circulation Research [Ovid Technologies (Wolters Kluwer)]
卷期号:129 (5): 568-582 被引量:55
标识
DOI:10.1161/circresaha.120.318364
摘要

Background: Fibrotic cardiac remodeling is a maladaptive response to acute or chronic injury that leads to arrhythmia and progressive heart failure. The underlying mechanisms remain unclear. We performed high-throughput RNA sequencing to analyze circular RNA profile in human cardiac disease and developed transgenic mice to explore the roles of circNlgn. Methods and Results: Using RNA sequencing, we found that circular neuroligin RNA (circNlgn) was highly upregulated in myocardial tissues of patients with selected congenital heart defects with cardiac overload. Back-splicing of the neuroligin gene led to the translation of a circular RNA–derived peptide (Nlgn173) with a 9-amino-acid nuclear localization motif. Binding of this motif to the structural protein LaminB1 facilitated the nuclear localization of Nlgn173. CHIP analysis demonstrated subsequent binding of Nlgn173 to both ING4 (inhibitor of growth protein 4) and C8orf44-SGK3 (serum and glucocorticoid-inducible kinase-3) promoters, resulting in aberrant collagen deposition, cardiac fibroblast proliferation, and reduced cardiomyocyte viability. Three-dimensional ultrasound imaging of circNlgn-transgenic mice showed impaired left ventricular function, with further impairment when subjected to left ventricular pressure overload compared with WT (wild type) mice. Nuclear translocation of Nlgn173, dysregulated expression of ING4 and C8orf44-SGK3, and immunohistochemical markers of cardiac fibrosis were detected in a panel of 145 patient specimens. Phenotypic changes observed in left ventricular pressure overload and transgenic mice were abrogated with silencing of circNlgn or its targets ING4 and SGK3. Conclusions: We show that a circular RNA can be translated into a novel protein isoform. Dysregulation of this process contributes to fibrosis and heart failure in cardiac overload–induced remodeling. This mechanism may hold therapeutic implications for cardiac disease.
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