小干扰RNA诱导组蛋白3赖氨酸27三甲基化的分子机制研究

Small RNA mediated gene silencing is a widely conserved gene regulation mechanism in eukaryotes. Early experiments have demonstrated that small RNAs can be applied to prohibit tumorigenesis and viral infection. However, we need understand the biogenesis, mechanism, and physiological roles of these small RNAs before their application in clinics and therapeutics. siRNAs can be transferred from the cytoplasm to the nucleus, inhibit transcriptions elongation, and induce H3K9 and H3K27 trimethylation to silence gene expression via a nuclear RNAi defective (Nrde) pathway in C. elegans. Yet the molecular mechanism of siRNA-induce H3K27me3 is unclear. Here, we propose to further investigate the molecular mechanism of small RNA-mediated gene silencing and the roles of the PRC2 complex and the H3K27 methyltransferase MES-2 by the combining of genetical, biochemical, and molecular means in C. elegans. This study will not only help us to understand the biology of small RNAs, but also help us to apply the RNAi technology to basic research and clinics.

RNA干扰是一个非常广泛而且保守的基因调节机制。早期试验已经成功地表明小RNA 可以用来抑制癌基因和病毒基因的表达。然而，在小RNA被用于临床和制药之前，我们必须正确地了解小RNA的产生机理，作用机制和体内功能等。Nrde通路转运siRNA从细胞质到细胞核并抑制转录的延伸，诱导组蛋白H3K9和H3K27的三甲基化，从而缄默基因表达。然而，NRDE复合物和siRNA如何造成组蛋白的H3K27的三甲基化的分子机制尚不清楚。本项目将围绕以上问题，进一步研究模式生物秀丽线虫中siRNA 调控基因表达的作用方式，通过遗传学、生化和分子生物学的方法研究PRC2复合物以及H3K27甲基转移酶MES-2在细胞核RNA干扰中的作用以及其分子机理。这项研究有助于我们更深入地了解小RNA指导的表观遗传和转录调控机制。从而不仅对理解RNA的基础生物学有重要意义，而且有助于更好地将RNA干扰技术用于研究和临床治疗。