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| Status |
Public on Mar 26, 2020 |
| Title |
Enhancing Cardiac Cell Proliferation and Survival Suppresses Dilated Cardiomyopathy caused by Ttn-insufficiency |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Dilated cardiomyopathy (DCM), defined by left ventricular (LV) enlargement associated with impaired cardiac performance, is a major cause of heart failure (HF). This results in a dilated, thin-walled left ventricle that fails to supply sufficient blood to the body. Truncating variants in TTN (TTNtv), coding for the largest structural protein in the sarcomere, contribute to the largest portion of familial and ambulatory DCM. The mechanisms for how TTNtv lead to cardiac dilation are unclear. Here, we show that reduction of Ttn expression by shRNA (Ttn shRNA) generated DCM in both mouse and rat. Ttn shRNA transduced mice developed typical DCM manifestations including impaired cardiac performance, enlarged LV and reduced LV wall thickness. Gene profiling indicates cardiac metabolism, cell proliferation and survival related genes are significantly dysregulated in Ttn shRNA-induced DCM. TUNEL assay showed Ttn shRNA induced a significant increase of cardiac cell apoptosis. A screen of 15 dysregulated downstream genes identified candidates, including Esrra, Esrrb and Yy1 significantly suppressed Ttn shRNA-induced cardiac dilation and/or DCM. Ttn shRNA induced cardiac cell apoptosis was ameliorated by Yy1. Importantly, by inducing D-type cyclin, Yy1 initiated cardiomyocyte cell cycle reentry facilitating the restoration of cardiac performance. Our findings demonstrate that DCM caused by Ttn insufficiency can be treated by therapeutically enhancing cardiac cell proliferation and survival.
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| Overall design |
In total, 7 RNA-seq samples were sequenced. 3 Controls and 4 Ttn-KO mice.
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| Contributor(s) |
Jianming J, Dan L |
| Citation(s) |
31705051 |
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| Submission date |
Mar 26, 2018 |
| Last update date |
Jun 25, 2020 |
| Contact name |
Roger Foo |
| Organization name |
Genome Institute of Singapore
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| Street address |
60 Biopolis Street
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| City |
Singapore |
| ZIP/Postal code |
138672 |
| Country |
Singapore |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA445651 |
| SRA |
SRP136441 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE112319_RAW.tar |
1.0 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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