整合的小 RNA、mRNA 和蛋白质组学揭示了一个 miRNA 网络，协调人类心脏发育的代谢成熟。

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.

背景：随着胎儿心脏的发育，心肌细胞增殖潜力降低，而脂肪酸氧化能力在一个高度调控的转变中增加，这个转变被称为心脏成熟。小非编码 RNA，如 microRNAs（miRNAs），有助于建立和控制组织特异性转录程序。然而，小 RNA 表达动态和控制人类胎儿心脏成熟的全基因组 miRNA 调控网络仍知之甚少。

结果：对小 RNA 的转录组谱分析揭示了 miRNA、piRNA、circRNA、snoRNA、snRNA 和 tRNA 在 8 至 19 周龄妊娠期间发育中的人类心脏的时间表达模式。我们的分析表明，miRNAs 是整个妊娠中期最具动态表达的小 RNA 种类。差异表达的 miRNA 和 mRNA 的交叉参考预测了 6200 个 mRNA 靶标，其中 2134 个随着妊娠的进展而上调，4066 个下调。此外，我们发现上调 miRNA 的下调靶标，包括 hsa-let-7b、miR-1-3p、miR-133a-3p、miR-143-3p、miR-499a-5p 和 miR-30a-5p，主要控制细胞周期进程。相比之下，下调 miRNA 的上调靶标，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，揭示了 mRNA 靶标编码的蛋白质及其相关代谢物介导脂肪酸氧化，并在心脏发育过程中富集。

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，整个妊娠中期 miRNA 表达的协调激活和抑制对于建立一个动态的 miRNA-mRNA-蛋白质网络是至关重要的，该网络降低了心肌细胞增殖潜力，同时增加了成熟人类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调控提供了新的见解。