背景:随着胎儿心脏的发育,在称为心脏成熟的高度调节的转变中,心肌细胞增殖潜能降低,而脂肪酸氧化能力增加。小的非编码RNA,如microRNAs(miRNAs),有助于组织特异性转录程序的建立和控制。然而,小RNA表达动力学和控制人类胎儿心脏成熟的全基因组miRNA调控网络仍然知之甚少。
结果:小RNA的转录组分析揭示了miRNA的时间表达模式,piRNA,circRNA,snoRNA,在妊娠8至19周之间发育中的人类心脏中的snRNA和tRNA。我们的分析表明,miRNAs在整个妊娠中期是最动态表达的小RNA种类。交叉引用差异表达的miRNA和mRNA预测6200个mRNA靶标,随着妊娠的进展,其中2134例上调,4066例下调。此外,我们发现上调的miRNA的下调靶标,包括hsa-let-7b,miR-1-3p,miR-133a-3p,miR-143-3p,miR-499a-5p,miR-30a-5p主要控制细胞周期进程。相比之下,上调下调miRNA的靶标,包括hsa-miR-1276,miR-183-5p,miR-1229-3p,miR-615-3p,miR-421,miR-200b-3p和miR-18a-3p,与能量感应和氧化代谢有关。此外,将miRNA和mRNA谱与蛋白质组和报告代谢物整合显示,mRNA靶标中编码的蛋白质及其相关代谢物介导脂肪酸氧化,并随着心脏发育而富集.
结论:本研究首次全面分析了成熟人类胎儿心脏的小RNA组。我们的发现表明,在整个妊娠中期,miRNA表达的协调激活和抑制对于建立动态的miRNA-mRNA-蛋白质网络至关重要,该网络可降低心肌细胞增殖潜力,同时增加成熟的人胎儿心脏的氧化能力。我们的结果为人类胎儿心脏代谢成熟的分子控制提供了新的见解。
BACKGROUND: As the fetal heart develops, cardiomyocyte proliferation potential decreases while fatty acid oxidative capacity increases in a highly regulated transition known as cardiac maturation. Small noncoding RNAs, such as microRNAs (miRNAs), contribute to the establishment and control of tissue-specific transcriptional programs. However, small RNA expression dynamics and genome-wide miRNA regulatory networks controlling maturation of the human fetal heart remain poorly understood.
RESULTS: Transcriptome profiling of small RNAs revealed the temporal expression patterns of miRNA, piRNA, circRNA, snoRNA, snRNA and tRNA in the developing human heart between 8 and 19 weeks of gestation. Our analysis demonstrated that miRNAs were the most dynamically expressed small RNA species throughout mid-gestation. Cross-referencing differentially expressed miRNAs and mRNAs predicted 6200 mRNA targets, 2134 of which were upregulated and 4066 downregulated as gestation progressed. Moreover, we found that downregulated targets of upregulated miRNAs, including hsa-let-7b, miR-1-3p, miR-133a-3p, miR-143-3p, miR-499a-5p, and miR-30a-5p predominantly control cell cycle progression. In contrast, upregulated targets of downregulated miRNAs, including hsa-miR-1276, miR-183-5p, miR-1229-3p, miR-615-3p, miR-421, miR-200b-3p and miR-18a-3p, are linked to energy sensing and oxidative metabolism. Furthermore, integrating miRNA and mRNA profiles with proteomes and reporter metabolites revealed that proteins encoded in mRNA targets and their associated metabolites mediate fatty acid oxidation and are enriched as the heart develops.
CONCLUSIONS: This study presents the first comprehensive analysis of the small RNAome of the maturing human fetal heart. Our findings suggest that coordinated activation and repression of miRNA expression throughout mid-gestation is essential to establish a dynamic miRNA-mRNA-protein network that decreases cardiomyocyte proliferation potential while increasing the oxidative capacity of the maturing human fetal heart. Our results provide novel insights into the molecular control of metabolic maturation of the human fetal heart.