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| Status |
Public on Apr 07, 2024 |
| Title |
DEAD-box helicase 17 (DDX17) protects cardiac function by promoting mitochondrial homeostasis in heart failure |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
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| Summary |
DEAD box 17 (DDX17) is a typical member of the DEAD box family with transcriptional cofactor activity. Although DDX17 is abundantly expressed in the myocardium, its role in the heart is not fully understood. We generated cardiomyocyte-specific Ddx17-knockout mice and cardiomyocyte-specific Ddx17 transgenic mice and explored the function of DDX17 using various cardiomyocyte injury and heart failure (HF) models. We also validated the correlation between DDX17 expression and cardiac function in myocardial biopsy samples from HF patients. DDX17 was downregulated in myocardial samples from HF mouse models and cardiomyocyte injury models. We found that the cardiomyocyte-specific knockout of DDX17 promotes autophagic flux blockage and cardiomyocyte apoptosis in pathological conditions, resulting in progressive heart dysfunction, thereby leading to maladaptive remodeling and progression of HF. The replenishment of DDX17 in cardiomyocytes protected heart function in pathological conditions. Further studies showed that DDX17 can bind to the transcriptional repressor BCL6 and inhibit the expression of the mitochondrial fission protein DRP1. When DDX17 expression was decreased, the transcriptional repression of BCL6 was reduced, resulting in increased DRP1 expression and mitochondrial fission, which caused autophagy flux blockage and apoptosis in cardiomyocytes, leading to impaired mitochondrial homeostasis and HF. We also verified the clinical correlation of DDX17 expression with cardiac function and DRP1 expression in endomyocardial biopsies from patients with HF. These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway during HF.
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| Overall design |
We collected NMVMs (neonatal mouse ventricular myocytes) from two groups of mouse hearts (three biological replications in each group). These two groups were labelled as 'TG-minus (Con)' (which meant the wild-type littermates of Ddx17-transgenic C57BL/6 male mice were used in the research, NTGM1-3) and 'TG-plus (Ddx-17 TG)' (which meant cardiac-specific Ddx17-transgenic overexpression mice generated by standard CRISPR/Cas9 techniques, NTGP1-3). To explore the molecular mechanisms through which DDX17 inhibits mitochondrial fission and promotes mitochondrial fusion, we applied the nucleosome occupancy and methylome sequencing (NOMe-seq) in these samples.
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| Contributor(s) |
Zheng Y |
| Citation(s) |
38782919 |
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| Submission date |
Aug 30, 2020 |
| Last update date |
Jun 05, 2024 |
| Contact name |
Yuxuan Zheng |
| Organization name |
Fudan University
|
| Street address |
825 Zhangheng Rd.
|
| City |
Shanghai |
| ZIP/Postal code |
201203 |
| Country |
China |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA660244 |
| SRA |
SRP279346 |
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