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Neely, G.G.* ; Kuba, K.* ; Cammarato, A.* ; Isobe, K.* ; Amann, S.* ; Zhang, L.Y.* ; Murata, M.* ; Elmen, 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.*

A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function.

Cell 141, 142-153 (2010)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cause cardiac-arrhythmias; QT interval duration; Cardiovascular-disease; CCR4-not complex; Common variants; Gene; Mutations; Dysfunction; Channels; Failure
Language english
Publication Year 2010
HGF-reported in Year 2010
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 141, Issue: 1, Pages: 142-153 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
PubMed ID 20371351
DOI 10.1016/j.cell.2010.02.023
Scopus ID 77950946233
Erfassungsdatum 2010-10-15
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