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Citation
Neely, G.G., Kuba, K., Cammarato, A., Isobe, K., Amann, S., Zhang, L., Murata, M., Elmén, L., Gupta, V., Arora, S., Sarangi, R., Dan, D., Fujisawa, S., Usami, T., Xia, C.P., Keene, A.C., Alayari, N.N., Yamakawa, H., Elling, U., Berger, C., Novatchkova, M., Koglgruber, R., Fukuda, K., Nishina, H., Isobe, M., Pospisilik, J.A., Imai, Y., Pfeufer, A., Hicks, A.A., Pramstaller, P.P., Subramaniam, S., Kimura, A., Ocorr, K., Bodmer, R., Penninger, J.M. (2010). A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function.  Cell 141(1): 142--153.
FlyBase ID
FBrf0210524
Publication Type
Research paper
Abstract
Heart diseases are the most common causes of morbidity and death in humans. Using cardiac-specific RNAi-silencing in Drosophila, we knocked down 7061 evolutionarily conserved genes under conditions of stress. We present a first global roadmap of pathways potentially playing conserved roles in the cardiovascular system. One critical pathway identified was the CCR4-Not complex implicated in transcriptional and posttranscriptional regulatory mechanisms. Silencing of CCR4-Not components in adult Drosophila resulted in myofibrillar disarray and dilated cardiomyopathy. Heterozygous not3 knockout mice showed spontaneous impairment of cardiac contractility and increased susceptibility to heart failure. These heart defects were reversed via inhibition of HDACs, suggesting a mechanistic link to epigenetic chromatin remodeling. In humans, we show that a common NOT3 SNP correlates with altered cardiac QT intervals, a known cause of potentially lethal ventricular tachyarrhythmias. Thus, our functional genome-wide screen in Drosophila can identify candidates that directly translate into conserved mammalian genes involved in heart function.
Graphical Abstract
Obtained with permission from Cell Press.
PubMed ID
PubMed Central ID
PMC2855221 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Cell
    Title
    Cell
    Publication Year
    1974-
    ISBN/ISSN
    0092-8674
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