1. RNA Sequence Analyses throughout the Course of Mouse Cardiac Laminopathy Identify Differentially Expressed Genes for Cell Cycle Control and Mitochondrial Function.
- Author
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Shao, Zhili, Koh, Wonshill, Ni, Ying, Li, Wei, Agatisa-Boyle, Brendan, Merkurjev, Daria, and Tang, Wai Hong Wilson
- Subjects
RNA sequencing ,CELL cycle ,CARDIOMYOPATHIES ,GENETIC mutation ,OXIDATIVE phosphorylation ,DISEASE progression - Abstract
Lamin A/C (LMNA) gene mutations are a known cause of familial dilated cardiomyopathy, but the precise mechanisms triggering disease progression remain unknown. We hypothesize that analysis of differentially expressed genes (DEGs) throughout the course of Lmna knockout (Lmna
−/− )-induced cardiomyopathy may reveal novel Lmna-mediated alterations of signaling pathways leading to dilated cardiomyopathy. Although Lmna was the only DEG down-regulated at 1 week of age, we identified 730 and 1004 DEGs in Lmna−/− mice at 2 weeks and 1 month of age, respectively. At 2 weeks, Lmna−/− mice demonstrated both down- and up-regulation of the key genes involving cell cycle control, mitochondrial dysfunction, and oxidative phosphorylation, as well as down-regulated genes governing DNA damage repair and up-regulated genes involved in oxidative stress response, cell survival, and cardiac hypertrophy. At 1 month, the down-regulated genes included those involved in oxidative phosphorylation, mitochondrial dysfunction, nutrient metabolism, cardiac β-adrenergic signaling, action potential generation, and cell survival. We also found 96 overlapping DEGs at both ages involved in oxidative phosphorylation, mitochondrial function, and calcium signaling. Impaired oxidative phosphorylation was observed at early disease stage, even before the appearance of disease phenotypes, and worsened with disease progression, suggesting its importance in the pathogenesis and progression of LMNA cardiomyopathy. Reduction of oxidative stress might therefore prevent or delay the development from Lmna mutation to LMNA cardiomyopathy. [ABSTRACT FROM AUTHOR]- Published
- 2020
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