线粒体非编码RNA(ncRNA)生物学功能的研究

Non-coding RNAs (ncRNAs) represent the vast majority of RNA transcripts in the cells that are non-protein-coding and function as critical transcriptional and post-transcriptional regulators. To date the studies of ncRNAs have identified and been mainly focused on a variety of nuclear and cytoplasmic ncRNAs, however, little is known about those that are located in cellular organelles. Mitochondria are unique subcellular organelles that have principal function of energy production and contain their own genome. It has been reported that a large number of ncRNAs do exist in mitochondria and play important roles in cell proliferation, differentiation and development. Dysregulation of mitochondrial ncRNAs has been shown to be associated with mitochondrial diseases and tumor development. However, the underlying molecular mechanisms remain to be elucidated. Investigation of mitochondrial ncRNAs has become an interesting and attractive research field. In order to understand the functional roles of mitochondrial ncRNAs, in the current study, we aim to address 1) How are mitochondrial ncRNAs encoded and regulated? 2) What's the role of mitochondrial ncRNAs in mitochondrial biogenesis and functions? 3) What's the role of mitochondrial ncRNAs in cellular functions? At the end, we will investigate the expression of mitochondrial ncRNAs in mitochondrial diseases and tumor samples. We believe the current study will help to understand the biological functions of ncRNAs and provide insights into the molecular mechanisms underlying human diseases, which can eventually help with the diagnosis and therapy of diseases.

非编码RNA（non-coding RNA，ncRNA）是细胞中广泛存在的、在转录或转录后水平上对基因表达起关键调节作用的、不编码蛋白的RNA。迄今为止的研究主要集中于核及胞质内的ncRNA上，对细胞器ncRNA的报道甚少。线粒体是特殊的细胞器，是能量产生的主要场所，且带有自身的基因组。事实上线粒体中也存在大量的ncRNA，它们在细胞生长、分化和发育过程中起重要作用。线粒体ncRNA的表达和功能的失调被证实与线粒体疾病和肿瘤相关。线粒体ncRNA的研究已成为近年来一个很有吸引力的研究领域。本课题拟系统地研究人类细胞线粒体ncRNA的来源和产生的调节；并对它们的生物学功能，包括对线粒体的生物合成和功能及对细胞功能的作用进行研究。最后，分析它们可能的调控途径，并检测它们在线粒体疾病和肿瘤中的表达情况。本课题的开展可为进一步探讨疾病的分子机理、为ncRNA在疾病诊断和治疗中的应用提供理论依据。

非编码RNA（non-coding RNA，ncRNA）是不编码蛋白的RNA，对ncRNA表达和功能的研究是表观遗传学的主要内容之一。微RNA (microRNA，miRNA)是一类小的ncRNA,它们通过结合到靶基因mRNA的3’-UTR来抑制其翻译或引起其降解，从而在转录后水平调控基因的表达。miRNA在细胞生长、分化和发育过程中起重要作用。线粒体中存在大量的miRNA，它们的表达和功能的失调与线粒体疾病和肿瘤的发生发展密切相关。Dicer是miRNA合成的关键酶之一。本课题的研究内容主要包括：筛选受Dicer调节的线粒体miRNA；对它们的生物学功能进行初步的研究；并分析它们可能的调控途径，探讨受Dicer调节的miRNA以及其它表观遗传因素在疾病特别是肿瘤中的作用机理。我们的研究结果表明：1)至少有18个来源于线粒体的miRNA受Dicer的表达调控，它们可能通过对靶基因的表达调控在线粒体生物合成及功能调控等途径中起重要作用。2)Dicer能够剪切非编码的7SL RNA,进而影响信号识别颗粒复合体(SRP)介导的蛋白定位及表达。miR-581靶向Dicer，通过调节7SL RNA的切割影响乙肝病毒表面抗原(HBsAg)的表达。3)Ras通过对RRAD基因启动子区甲基化水平的调节影响其活性，进一步影响RRAD对葡萄糖摄入途径的调控，最终影响肿瘤的形成。4)Dicer通过与SIRT7的直接相互作用，调节组蛋白H3K18的去乙酰化水平，形成对DNA损伤的应激反应。本课题的研究表明miRNA及其重要调节因子Dicer通过不同的调节机制在肿瘤等疾病的发生发展过程中起重要的作用，该研究可能为疾病诊断与治疗技术的开发提供理论依据。