tRNA fragments as transgenerational information carriers

描述(申请人提供)：从父母到后代的特征遗传是地球上生命的普遍特征，并对其内部运作和进化产生根本影响。表观遗传学领域的最新结果重新证明了曾经不可信的可能性，即父母的环境可能会对他们后代的表型产生影响。获得性遗传(即环境信息从一代传给下一代)通常被称为拉马克遗传，证明它的存在将极大地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。我使用微阵列方法来确定父亲环境对小鼠后代表型的跨代影响，将父亲的低蛋白饮食与后代的胆固醇代谢联系起来。在这个项目中，我提议系统地描述环境导向型特征在老鼠身上遗传的机制。根据初步数据，低蛋白饮食似乎专门改变了精子中特定小RNA片段的水平，受精后这些RNA片段可以改变早期胚胎的基因表达程序。在这里，我建议结合遗传学、表观遗传学、细胞生物学和发育生物学的研究来研究这些RNA对饮食的反应产生的机制基础，并确定这些RNA对下一代的功能影响。这些研究将对从生殖生物学到进化再到流行病学的各个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.