Çiçek Ibrahim Ömer, Karaca Samir, Brankatschk Marko, Eaton Suzanne, Urlaub Henning, Shcherbata Halyna R
Max Planck Research Group of Gene Expression and Signaling, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Bioanalytical Mass Spectrometry Research Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Genetics. 2016 Mar;202(3):1167-83. doi: 10.1534/genetics.115.185371. Epub 2016 Jan 22.
Since the discovery of microRNAs (miRNAs) only two decades ago, they have emerged as an essential component of the gene regulatory machinery. miRNAs have seemingly paradoxical features: a single miRNA is able to simultaneously target hundreds of genes, while its presence is mostly dispensable for animal viability under normal conditions. It is known that miRNAs act as stress response factors; however, it remains challenging to determine their relevant targets and the conditions under which they function. To address this challenge, we propose a new workflow for miRNA function analysis, by which we found that the evolutionarily young miRNA family, the mir-310s (mir-310/mir-311/mir-312/mir-313), are important regulators of Drosophila metabolic status. mir-310s-deficient animals have an abnormal diet-dependent expression profile for numerous diet-sensitive components, accumulate fats, and show various physiological defects. We found that the mir-310s simultaneously repress the production of several regulatory factors (Rab23, DHR96, and Ttk) of the evolutionarily conserved Hedgehog (Hh) pathway to sharpen dietary response. As the mir-310s expression is highly dynamic and nutrition sensitive, this signal relay model helps to explain the molecular mechanism governing quick and robust Hh signaling responses to nutritional changes. Additionally, we discovered a new component of the Hh signaling pathway in Drosophila, Rab23, which cell autonomously regulates Hh ligand trafficking in the germline stem cell niche. How organisms adjust to dietary fluctuations to sustain healthy homeostasis is an intriguing research topic. These data are the first to report that miRNAs can act as executives that transduce nutritional signals to an essential signaling pathway. This suggests miRNAs as plausible therapeutic agents that can be used in combination with low calorie and cholesterol diets to manage quick and precise tissue-specific responses to nutritional changes.
自二十年前发现微小RNA（miRNA）以来，它们已成为基因调控机制的重要组成部分。miRNA具有看似矛盾的特征：单个miRNA能够同时靶向数百个基因，而在正常条件下其存在对于动物的生存大多是可有可无的。已知miRNA作为应激反应因子发挥作用；然而，确定其相关靶标以及它们发挥作用的条件仍然具有挑战性。为应对这一挑战，我们提出了一种新的miRNA功能分析工作流程，通过该流程我们发现，在进化上较新的miRNA家族，即mir-310s（mir-310/mir-311/mir-312/mir-313），是果蝇代谢状态的重要调节因子。mir-310s缺陷型动物对于众多饮食敏感成分具有异常的饮食依赖性表达谱，会积累脂肪，并表现出各种生理缺陷。我们发现，mir-310s同时抑制进化上保守的Hedgehog（Hh）信号通路的几种调节因子（Rab23、DHR96和Ttk）的产生，以增强饮食反应。由于mir-310s的表达具有高度动态性且对营养敏感，这种信号传递模型有助于解释控制Hh信号对营养变化快速而强烈反应的分子机制。此外，我们在果蝇中发现了Hh信号通路的一个新成分Rab23，它在生殖系干细胞微环境中自主调节Hh配体的运输。生物体如何适应饮食波动以维持健康的体内平衡是一个有趣的研究课题。这些数据首次报道了miRNA可以作为将营养信号转导至重要信号通路的执行者。这表明miRNA可能是合理的治疗剂，可与低热量和低胆固醇饮食联合使用，以管理对营养变化的快速而精确的组织特异性反应。
