Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep28592
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Funding
- Japan Society for the Promotion of Science through the Funding Program for Next Generation World-Leading Researchers (NEXT Program)
- Japanese Ministry of Health, Labor, and Welfare
- Japanese Ministry of Education, Culture, Sports, Science, and Technology
- Japan Society for the Promotion of Science
- Takeda Science Foundation
- Japan Heart Foundation
- Japan Cardiovascular Research Foundation
- Japan Intractable Diseases Research Foundation
- Japan Foundation of Applied Enzymology
- Japan Medical Association
- Uehara Memorial Foundation
- Mochida Memorial Foundation
- Banyu Foundation
- Naito Foundation
- Inoue Foundation for Science
- Osaka Medical Research foundation
- Ichiro Kanehara Foundation
- Showa Houkoukai
- Grants-in-Aid for Scientific Research [16K09501, 15H04820, 15H04821] Funding Source: KAKEN
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Under hypertrophic stimulation, cardiomyocytes enter a hypermetabolic state and accelerate biomass accumulation. Although the molecular pathways that regulate protein levels are well-studied, the functional implications of RNA accumulation and its regulatory mechanisms in cardiomyocytes remain elusive. Here, we have elucidated the quantitative kinetics of RNA in cardiomyocytes through single cell imaging and c-Myc (Myc)-mediated hypermetabolic analytical model using cultured cardiomyocytes. Nascent RNA labeling combined with single cell imaging demonstrated that Myc protein significantly increased the amount of global RNA production per cardiomyocyte. Chromatin immunoprecipitation with high-throughput sequencing clarified that overexpressed Myc bound to a specific set of genes and recruits RNA polymerase II. Among these genes, we identified Btg2 as a novel target of Myc. Btg2 overexpression significantly reduced cardiomyocyte surface area. Conversely, shRNA-mediated knockdown of Btg2 accelerated adrenergic stimulus-induced hypertrophy. Using mass spectrometry analysis, we determined that Btg2 binds a series of proteins that comprise mRNA deadenylation complexes. Intriguingly, Btg2 specifically suppresses cytosolic, but not nuclear, RNA levels. Btg2 knockdown further enhances cytosolic RNA accumulation in cardiomyocytes under adrenergic stimulation, suggesting that Btg2 negatively regulates reactive hypertrophy by negatively regulating RNA accumulation. Our findings provide insight into the functional significance of the mechanisms regulating RNA levels in cardiomyocytes.
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