关键词: bioinformatics analysis hypertrophic cardiomyopathy microarrays nuclear-encoded mitochondrial genes transcription factors

来  源:   DOI:10.3389/fgene.2021.670787   PDF(Pubmed)

Abstract:
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease and mitochondria plays a key role in the progression in HCM. Here, we analyzed the expression pattern of nuclear-encoded mitochondrial genes (NMGenes) in HCM and found that the expression of NMGenes was significantly changed. A total of 316 differentially expressed NMGenes (DE-NMGenes) were identified. Pathway enrichment analyses showed that energy metabolism-related pathways such as \"pyruvate metabolism\" and \"fatty acid degradation\" were dysregulated, which highlighted the importance of energy metabolism in HCM. Next, we constructed a protein-protein interaction network based on 316 DE-NMGenes and identified thirteen hubs. Then, a total of 17 TFs (transcription factors) were predicted to potentially regulate the expression of 316 DE-NMGenes according to iRegulon, among which 8 TFs were already found involved in pathological hypertrophy. The remaining TFs (like GATA1, GATA5, and NFYA) were good candidates for further experimental verification. Finally, a mouse model of transverse aortic constriction (TAC) was established to validate the genes and results showed that DDIT4, TKT, CLIC1, DDOST, and SNCA were all upregulated in TAC mice. The present study represents the first effort to evaluate the global expression pattern of NMGenes in HCM and provides innovative insight into the molecular mechanism of HCM.
摘要:
肥厚型心肌病(HCM)是一种常染色体显性遗传病,线粒体在HCM的进展中起着关键作用。这里,我们分析了核编码线粒体基因(NMGenes)在HCM中的表达模式,发现NMGenes的表达发生了显着变化。鉴定了总共316种差异表达的NMGene(DE-NMGene)。途径富集分析表明,能量代谢相关途径如“丙酮酸代谢”和“脂肪酸降解”失调,强调了HCM能量代谢的重要性。接下来,我们基于316DE-NMGenes构建了一个蛋白质-蛋白质相互作用网络,并确定了13个中心。然后,预测总共17个TFs(转录因子)可能根据iPregion调节316DE-NMGenes的表达,其中已发现8种TFs与病理性肥大有关。其余的TF(如GATA1、GATA5和NFYA)是进一步实验验证的良好候选者。最后,建立小鼠横主动脉缩窄(TAC)模型,对其基因进行验证,结果表明DDIT4、TKT、CLIC1,DDOST,和SNCA在TAC小鼠中均上调。本研究代表了评估NMGenes在HCM中的整体表达模式的第一个努力,并提供了对HCM分子机制的创新见解。
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