tRNA fragments as transgenerational information carriers

描述（由申请人提供）：从父母到后代的性状遗传是地球上生命的普遍特征，并对其内部运作和进化具有根本性的影响。表观遗传学领域的最新研究结果使人们重新认识到，父母的环境可能会影响其后代的表型。获得性特征的遗传（即环境信息从一代传递到下一代）通常被称为“拉马克”遗传，它的存在将彻底改变我们对进化的看法，以及人类流行病学研究的进行方式。我已经使用了微阵列的方法来确定父系环境对小鼠后代表型的跨代影响，将父系低蛋白饮食与后代的胆固醇代谢联系起来。在这个项目中，我建议系统地描述环境导向性状在小鼠中遗传的机制。基于初步数据，低蛋白饮食似乎特异性地改变了精子中特定小RNA片段的水平，并且在受精后，这些RNA片段可以改变早期胚胎中的基因表达程序。在这里，我提出了一个遗传，表观遗传，细胞生物学和发育生物学研究相结合，以调查这些RNA在饮食反应中产生的机制基础，并确定这些RNA对下一代的功能后果。这些研究将对生殖生物学、进化论和流行病学等领域产生革命性的影响。

DESCRIPTION (provided by applicant): The inheritance of traits from parent to offspring is a universal characteristic of life on earth, and has fundamental consequences for its inner workings, and for evolution. Recent results in the field of epigenetics have resurrected the once-discredited possibility that the environment of parents could have an effect on the phenotype of their offspring. Inheritance of acquired characters (ie passage of environmental information from one generation to the next) is often called "Lamarckian" inheritance, and demonstration of its existence would drastically alter how we think about evolution, and how human epidemiological studies are carried out. I have used a microarray approach to identify transgenerational effects of the paternal environment on offspring phenotype in mice, linking paternal low protein diet to cholesterol metabolism in offspring. In this project I propose to systematically characterize the mechanism by which environmentally-directed traits are inherited in mice. Based on preliminary data, it appears that low protein diet specifically alters the levels of specific small RNA fragments in sperm, and that after fertilization these RNA fragments can alter gene expression programs in the early embryo. Here, I propose a combination of genetic, epigenetic, cell biology, and developmental biology studies to investigate the mechanistic basis for generation of these RNAs in response to diet, and to determine the functional consequences of these RNAs for the next generation. These studies will have a revolutionary impact on fields ranging from reproductive biology to evolution to epidemiology.