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CRISPR Activation Reverses Haploinsufficiency and Functional Deficits Caused by TTN Truncation Variants

ABSTRACT: TTN CRISPR activation rescued TTNtv-related functional deficits despite increasing truncated TTN levels, which provides evidence to support haploinsufficiency as a relevant genetic mechanism underlying heterozygous TTNtvs (TTN truncation variants). CRISPR activation could be developed as a therapeutic to treat a large proportion of TTNtvs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255814 | GEO | 2024/02/15

REPOSITORIES: GEO

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Enhancing Cardiac Cell Proliferation and Survival Suppresses Dilated Cardiomyopathy caused by Ttn-insufficiency

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Promoter or enhancer activation by CRISPRa rescues haploinsufficiency caused obesity

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Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [scRNA-seq]

Project description: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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Titin truncating variantsin hiPSC-cardiomyocytes inducepathogenic proteinopathy, sarcomeredefect and contractile dysfunction independent of the core contractilemachinery [bulk RNA-seq]

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Project description:Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice heterozygous for the orthologous factor, although the source of this discrepancy is unknown. The inability to accurately model human disease in mice impedes the study of complex phenotypes and critically limits the discovery and testing of potential therapeutics. Laboratory mice have longer telomeres (>40 kilobases (kb)) compared to humans (~5-15 kb), potentially protecting them from age-related disease caused by haploinsufficiency. In humans, heterozygous non-sense mutations in the transcription factor, NOTCH1 (N1), lead to severe age-dependent aortic valve (AV) calcification. However, mice heterozygous for N1 do not develop calcific AV disease (CAVD)5. Here, we show that telomere shortening is sufficient to elicit age-dependent cardiac valve disease in N1+/- mice that closely mimics the human disease and that progressive shortening correlates with severity of disease, extending to AV thickening in the neonate. N1 haploinsufficiency led to increased proliferation in valves that further reduced telomere length. Calcified AVs exhibited downregulation of osteoclast factors and upregulation of pro-calcific regulatory nodes concordant with gene network alterations in human N1 heterozygous endothelial cells. Dysregulated genes in valves were enriched for those that have promoters normally contacted by telomere looping. These findings reveal a critical role for telomere length in a mouse model of age-dependent human disease that may have broader implications and provides an in vivo model in which to test therapeutic candidates to prevent or delay the progression of CAVD.

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