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| Status |
Public on Jan 25, 2023 |
| Title |
Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [scRNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Titintruncating variants(TTNtv) have been identified as the single largestgenetic cause of dilated cardiomyopathy(DCM). In this studywe modeled the disease phenotypes of TTNtv-induced DCM in hiPSC-CMsusing CRISPR/Cas9 genome editing and tissue engineering technologies. Transcriptomic, cellular and micro-tissue studies revealed that TTNtv hiPSC-CMs displayed pathogenic proteinopathy, sarcomere defects, aberrant Na+channel activities and, most importantly, contractile dysfunction. These phenotypes establish a dual mechanism of poison peptide effect and haploinsufficiency that collectively contribute to DCM pathogenesis. On the other hand, TTNtv cellular defects did not interfere with normal function of the core contractile machinery, actin-myosin-troponin-Ca2+complex, and preserved the therapeutic mechanism of sarcomere modulators. Treatment of TTNtv cardiac micro-tissues with investigational sarcomere modulators augmented contractility and resulted in sustained transcriptomicchanges that promotereversalof DCM disease signatures, as revealed by single-cell RNA-seqanalysis.Taken together, our findings depict the underlying pathogenic mechanisms of TTNtv-induced DCMand demonstrate the validity of sarcomere modulators as potentialtherapeutic agentsfor this disease.
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| Overall design |
Single cell RNAseq was performed on wt and TTNtv/+ cardiomyocyte containing cardiac microwire cultures with and without AMG3360355 (troponin modulator) or AMG2591713 (myosin activator) treatment.
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| Contributor(s) |
Huang G, Wakefield D, Yamawaki T, Luo X, Zhang J, Vigneault P, Wang J, Bisaria A, Oliver O, Zhou H, Li C, Wang S, Hale C |
| Citation(s) |
36525964 |
| Submission date |
Sep 01, 2021 |
| Last update date |
Jan 26, 2023 |
| Contact name |
Tracy Yamawaki |
| E-mail(s) |
tyamawak@amgen.com
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| Organization name |
AMGEN, INC.
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| Street address |
1120 VETERANS BLVD.
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| City |
SOUTH SAN FRANCISCO |
| State/province |
California |
| ZIP/Postal code |
94080 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (7)
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| This SubSeries is part of SuperSeries: |
| GSE183218 |
Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery |
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| Relations |
| BioProject |
PRJNA759629 |
| SRA |
SRP335253 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE183217_RAW.tar |
2.3 Gb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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