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

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 road-map of pathways potentially playing conserved roles in the cardiovascular system. One critical pathway identified was the CCR4-Not complex implicated in transcriptional and post-transcriptional regulatory mechanisms. Silencing of the 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 lethal arrhythmias. Thus, our functional genome-wide screen in Drosophila can identify candidates that directly translate into conserved mammalian genes involved in heart function.

心脏病是人类发病和死亡的最常见原因。我们利用果蝇心脏特异性RNA干扰沉默技术，在应激条件下敲低了7061个进化上保守的基因。我们首次呈现了可能在心血管系统中发挥保守作用的通路的全局路线图。鉴定出的一个关键通路是CCR4 - Not复合物，它涉及转录和转录后调控机制。在成年果蝇中沉默CCR4 - Not组分导致肌原纤维排列紊乱和扩张型心肌病。杂合型not3基因敲除小鼠表现出心脏收缩力自发受损以及对心力衰竭的易感性增加。通过抑制组蛋白去乙酰化酶（HDACs）可逆转这些心脏缺陷，这表明与表观遗传染色质重塑存在机制上的联系。在人类中，我们发现一个常见的NOT3单核苷酸多态性（SNP）与心脏QT间期改变相关，而QT间期改变是致命性心律失常的一个已知原因。因此，我们在果蝇中进行的全基因组功能筛选能够识别出可直接转化为参与心脏功能的保守哺乳动物基因的候选基因。