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.
authors.affiliation: Institute of Molecular Biotechnology of Austrian Academy of Sciences, Dr. Bohr Gasse 3-5, A-1030 Vienna, Austria.
authors.forename: G Gregory
authors.initials: GG
authors.lastname: Neely
authors.forename: Keiji
authors.initials: K
authors.lastname: Kuba
authors.forename: Anthony
authors.initials: A
authors.lastname: Cammarato
authors.forename: Kazuya
authors.initials: K
authors.lastname: Isobe
authors.forename: Sabine
authors.initials: S
authors.lastname: Amann
authors.forename: Liyong
authors.initials: L
authors.lastname: Zhang
authors.forename: Mitsushige
authors.initials: M
authors.lastname: Murata
authors.forename: Lisa
authors.initials: L
authors.lastname: Elmén
authors.forename: Vaijayanti
authors.initials: V
authors.lastname: Gupta
authors.forename: Suchir
authors.initials: S
authors.lastname: Arora
authors.forename: Rinku
authors.initials: R
authors.lastname: Sarangi
authors.forename: Debasis
authors.initials: D
authors.lastname: Dan
authors.forename: Susumu
authors.initials: S
authors.lastname: Fujisawa
authors.forename: Takako
authors.initials: T
authors.lastname: Usami
authors.forename: Cui-ping
authors.initials: CP
authors.lastname: Xia
authors.forename: Alex C
authors.initials: AC
authors.lastname: Keene
authors.forename: Nakissa N
authors.initials: NN
authors.lastname: Alayari
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamakawa
authors.forename: Ulrich
authors.initials: U
authors.lastname: Elling
authors.forename: Christian
authors.initials: C
authors.lastname: Berger
authors.forename: Maria
authors.initials: M
authors.lastname: Novatchkova
authors.forename: Rubina
authors.initials: R
authors.lastname: Koglgruber
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Pospisilik
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Imai
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hicks
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: Sai
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Karen
authors.initials: K
authors.lastname: Ocorr
authors.forename: Rolf
authors.initials: R
authors.lastname: Bodmer
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000503:physiopathology; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000502:physiology*; D005260:Female; D055106:Genome-Wide Association Study; D006321:Heart / Q000196:embryology / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011401:Promoter Regions, Genetic; D034622:RNA Interference