@article{8a596edb26284546b35b701a1512cb03,
title = "A Global In Vivo Drosophila RNAi Screen Identifies NOT3 as a Conserved Regulator of Heart Function",
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.",
keywords = "Humdisease, RNA",
author = "Neely, {G. Gregory} and Keiji Kuba and Anthony Cammarato and Kazuya Isobe and Sabine Amann and Liyong Zhang and Mitsushige Murata and Lisa Elm{\'e}n and Vaijayanti Gupta and Suchir Arora and Rinku Sarangi and Debasis Dan and Susumu Fujisawa and Takako Usami and Xia, {Cui ping} and Keene, {Alex C.} and Alayari, {Nakissa N.} and Hiroyuki Yamakawa and Ulrich Elling and Christian Berger and Maria Novatchkova and Rubina Koglgruber and Keiichi Fukuda and Hiroshi Nishina and Mitsuaki Isobe and Pospisilik, {J. Andrew} and Yumiko Imai and Arne Pfeufer and Hicks, {Andrew A.} and Pramstaller, {Peter P.} and Sai Subramaniam and Akinori Kimura and Karen Ocorr and Rolf Bodmer and Penninger, {Josef M.}",
note = "Funding Information: We thank all members of our laboratories and the VDRC, the Bioscience Education Research Center (Akita University), and Vincent Chen for helpful discussions and excellent technical support. We thank Eric Olson for the Hand-Gal4 driver and Manfred Frasch for TinCΔ4-Gal4 driver stocks. We thank the members of the QTSCD consortium for valuable support and discussion. J.M.P. is supported by the IMBA, the Austrian Ministry of Science, a European Research Council Advanced Investigator grant, and EuGeneHeart. K.K. is supported by Kaken (21659198) from the Japanese Ministry of Science, the Medical Top Track Program, and the Japan Heart Foundation. G.G.N. was supported by a Marie Curie International Incoming Fellowship. A.C. was supported by a postdoctoral fellowship and K.O. by a Scientist Development Grant from the American Heart Association. R.B. was supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health. A.P. is supported by grants 01GR0803 and 01EZ0874 from the German Federal Ministry of Research, FSID-261/2008 from the UK Foundation for the Study of Infant Deaths, and YGEIA/1104/17 and ERYEX/0406/06 from the Cyprus Cardiovascular Disease Educational and Research Trust. Y.I. is supported by the Global Center of Excellence Program. ",
year = "2010",
month = apr,
doi = "10.1016/j.cell.2010.02.023",
language = "English (US)",
volume = "141",
pages = "142--153",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",
}