Disease models & mechanisms, 2020-07, Vol.13 (7)
2020
Details
- Autor(en) / Beteiligte
- Titel
- Silencing of CCR4-NOT complex subunits affects heart structure and function
- Ist Teil von
- Disease models & mechanisms, 2020-07, Vol.13 (7)
- Ort / Verlag
- England: The Company of Biologists Ltd
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- The identification of genetic variants that predispose individuals to cardiovascular disease and a better understanding of their targets would be highly advantageous. Genome-wide association studies have identified variants that associate with QT-interval length (a measure of myocardial repolarization). Three of the strongest associating variants (single-nucleotide polymorphisms) are located in the putative promotor region of , a gene encoding the central CNOT1 subunit of CCR4-NOT: a multifunctional, conserved complex regulating gene expression and mRNA stability and turnover. We isolated the minimum fragment of the promoter containing all three variants from individuals homozygous for the QT risk alleles and demonstrated that the haplotype associating with longer QT interval caused reduced reporter expression in a cardiac cell line, suggesting that reduced expression might contribute to abnormal QT intervals. Systematic siRNA-mediated knockdown of CCR4-NOT components in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) revealed that silencing and other CCR4-NOT genes reduced their proliferative capacity. Silencing also shortened action potential duration. Furthermore, the cardiac-specific knockdown of orthologs of CCR4-NOT genes ( and ) was either lethal or resulted in dilated cardiomyopathy, reduced contractility or a propensity for arrhythmia. Silencing , and also affected cardiac chamber size and contractility. Developmental studies suggested that and are required during cardiac remodeling from larval to adult stages. To summarize, we have demonstrated how disease-associated genes identified by GWAS can be investigated by combining human cardiomyocyte cell-based and whole-organism heart models. Our results also suggest a potential link of and to QT alterations and further establish a crucial role of the CCR4-NOT complex in heart development and function.This article has an associated First Person interview with the first author of the paper.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1754-8403eISSN: 1754-8411DOI: 10.1242/dmm.044727Titel-ID: cdi_doaj_primary_oai_doaj_org_article_111907e034e04c50a593fa2c9ad5841c
- Format
- –
- Schlagworte
- Action Potentials, Animals, Animals, Genetically Modified, arrhythmia, cardiomyocytes, Cardiovascular disease, Cell Proliferation, Cloning, cnot1, Dros, drosophila heart, Drosophila melanogaster - genetics, Drosophila melanogaster - metabolism, Drosophila Proteins - genetics, Drosophila Proteins - metabolism, Exoribonucleases - genetics, Exoribonucleases - metabolism, Experiments, Gene expression, Gene Expression Regulation, Developmental, Gene Silencing, Genetic engineering, Genome-Wide Association Study, Genomes, gwas, Haplotypes, Heart, Heart Rate, HeLa Cells, hipsc, Humans, Induced Pluripotent Stem Cells - metabolism, Induced Pluripotent Stem Cells - pathology, Insects, Intracellular Signaling Peptides and Proteins - genetics, Intracellular Signaling Peptides and Proteins - metabolism, Long QT Syndrome - genetics, Long QT Syndrome - metabolism, Long QT Syndrome - pathology, Long QT Syndrome - physiopathology, long-qt syndrome, Morphogenesis, Myocytes, Cardiac - metabolism, Myocytes, Cardiac - pathology, Quality control, Repressor Proteins - genetics, Repressor Proteins - metabolism, Ribonucleases - genetics, Ribonucleases - metabolism, RNA-Binding Proteins - genetics, RNA-Binding Proteins - metabolism, Transcription Factors - genetics, Transcription Factors - metabolism