中文摘要：

生物体内存在大量的不编码蛋白质序列的非编码RNA（noncoding RNA，ncRNA），这些非编码RNA广泛参与生命活动的各个过程，包括基因表达调控、基因组稳定性维持、抵抗外源核酸侵染、发育的时序调节以及肿瘤发生等．越来越多的证据表明一系列重大疾病的发生、发展与这些非编码RNA的产生和调控失衡相关．小调节性RNA正在成为潜在的疾病标志物、药物靶点和生物分子药物．我们的研究主要集中在高等多细胞生物中细胞核里小干扰RNA调控基因表达的分子机制和生物学功能．我们在模式生物秀丽线虫中通过遗传筛选的方法发现了一条小干扰RNA在细胞核内调控基因表达的通路，以及参与这条通路的几个关键的细胞核RNA干扰缺陷型基因（nuclear RNAi defective，Nrde）．这一发现不仅解决了高等多细胞生物中细胞核内是否存在小RNA干扰现象的争论，而且发现小RNA可能通过主动转运的方式进入细胞核并调控RNA聚合酶Ⅱ（RNAP1I）介导的转录延伸．这一通路还可能参与了生物体的获得性遗传过程．本文重点阐述这一小干扰RNA调控基因表达的分子机制，并提出未来亟待解决的科学问题和发展方向．

英文摘要：

Noncoding RNAs （ncRNAs） are widely present in higher eukaryotes and involved in a range of biological processes to regulate gene expression, genome integrity, and development. Growing evidence has emerged that ncRNAs are also involved in the generation of diseases. Small regulatory RNAs have shown potential as disease marker, drug targets, and therapeutic drugs. Our research is focused on the molecular mechanism and biological roles of small interfering RNA （siRNA）-regulated gene expression in metazoans. By conducting genetic screenings in the model organism C. elegans, a novel nuclear RNAi defective （Nrde） pathway and the critical players have been identified through which siRNA performs gene silencing in the nucleus. This work not only demonstrated that nuclear RNAi machinery exists in metazoans, but also led to several discoveries. For example, we found that small RNAs are sorted between distinct subcellular compartments by associating with particular Argonaute proteins, siRNAs regulate transcription elongation by inhibiting RNA polymerase H and elicit premature termination. Furthermore, it was found that this pathway is necessary for the transgenerational maintenance of acquired RNAi.