Abstract
Heart maturation is an essentially biological process for neonatal heart transition to adult heart, thus illustrating the mechanism of heart maturation may be helpful to explore postnatal heart development and cardiac cardiomyopathy. This study combined proteomic analysis based on isobaric tags for relative and absolute quantitation (iTRAQ) and transcriptome analysis based on RNA sequencing to detect the proteins and genes associated with heart maturation in mice. The proteogenomics integrating analysis identified 254 genes/proteins as commonly differentially expressed between neonatal and adult hearts. Functional and pathway analysis demonstrated that these identified genes/proteins contribute to heart maturation mainly by regulating mRNA processing and energy metabolism. Genome-wide alternative splicing (AS) analysis showed that some important sarcomere and energy-associated genes undergo different AS events. Through the Cytoscape plug-in CytoHubba, a total of 23 hub genes were found and further confirmed by RT-qPCR. Next, we verified that the most up-regulated hub gene, Ogdhl, plays an essential role in heart maturation by detecting energy metabolism phenotype changes in the Ogdhl-interfering cardiomyocytes. Together, we revealed a complex gene network, AS genes and patterns, and candidate hub genes controlling heart maturation by proteome and transcriptome combination analysis.
Highlights
The vertebrate heart is the first organ to form during the process of embryogenesis [1]
34,236 unique peptides were generated, and 3667 proteins were identified. Among all these detected proteins, 2287 proteins were commonly expressed in P0 and postnatal 60 days (P60) hearts, while 966 proteins were expressed in P0, and 173 proteins in P60 hearts (Figure 1A)
Our study found that several sarcomere and energy metabolism associated genes, myosin heavy polypeptide 7 (Myh7), Atp5j, mitochondrial pyruvate carrier 1 (Mpc1), and coenzyme Q8A (Coq8a), undergo different alternative splicing (AS) events during neonatal and adult heart transition, and AS-altered expression changed more dramatic at protein levels than transcriptome levels
Summary
The vertebrate heart is the first organ to form during the process of embryogenesis [1]. Perinatal cardiac growth forms the four ventricular chambers, but the fetal heart cannot efficiently afford the hemodynamic and body growth demands after birth [2]. The fetal–adult heart maturation mainly includes four aspects, structural maturation, functional maturation, cell-cycle maturation, and metabolism maturation. Structural maturation increases myofibril alignment promoting contractile force and functional maturation. Functional maturation requires the heart to use energy more efficiently, driving energy maturation acceleration. Structure and functional maturation limit cardiomyocyte depolymerization, enhancing difficulty for cell division and promoting cell cycle maturation. Metabolism maturation often improves the sarcomeric structure and inhibits the cell cycle, leading structure and cell cycle maturation. Cell cycle maturation accelerated sarcomere alignments and structure maturation, leading energy maturation. The heart maturation processes might interact in co-regulated circuits, and a common regulatory mechanism may exist to control heart maturation
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