Biogenesis and Function of Regulatory RNAs

项目摘要 在过去的十年里，成千上万的非编码RNA（ncRNA）被发现是潜在的 基因表达的调节器。在这一组中，microRNAs（miRNAs）已成为必不可少的 转录后基因调控的介质，以及特定miRNA途径的缺陷， 与许多人类疾病有关。虽然对miRNAs如何表达和 功能已经实现，关于miRNA生物发生调控的突出问题， 目标识别仍有待解决。特别是，miRNA途径已被证明在细胞内起作用。 在不同的应激反应中起重要作用，但控制miRNA表达的机制， 对非理想条件下的活性知之甚少。秀丽隐杆线虫具有 被证明是在生物体水平上研究miRNA生物学的有利模型。的 开发灵敏的生化方法，独特的蠕虫菌株和强大的计算 pipelines使人们对miRNA的表达和靶向有了新的认识， 发展中的动物这些方法现在被用来了解miRNAs如何发挥作用 对热应激的反应。此外，许多新的长非编码RNA （lncRNA）被发现是由热休克诱导的，其中一种已经被证明是 在这种压力下生存。因此，多种ncRNA途径可能有助于 基因表达的变化需要生存这种压力条件。拟议的研究是 专注于阐明特定的miRNAs和lncRNAs的表达是如何被热调节的， 休克，反过来，这些ncRNA如何在这种压力下保护生物体。来 未来5年，这些研究有可能揭示ncRNA在热反应中的新作用 休克和设置阶段，研究ncRNA途径的影响，在生物体的反应 其他压力，包括疾病状态。工作旨在了解如何3'聚（A）尾巴上 信使RNA（mRNAs）有助于通过miRNA复合物的结合和调节，导致 令人惊讶的发现是，短poly（A）尾通常与高表达基因相关， 体细胞因此，一个新的研究方向解决了以前未被认识到的复杂性， poly（A）尾长控制及其与基因表达调控的关系。远景目标 这项研究计划的目的是为ncRNA和调控元件如何在 mRNA，如poly（A）尾，在不同条件下控制生物体基因表达。 此外，从这些研究中获得的知识有可能对 用于治疗人类疾病的基于RNA的治疗剂的设计和利用。

PROJECT SUMMARY Over the past decade, thousands of non-coding RNAs (ncRNAs) have been discovered as potential regulators of gene expression. Within this group, microRNAs (miRNAs) have emerged as essential mediators of post-transcriptional gene regulation, and defects in specific miRNA pathways have been linked to numerous human diseases. While a basic understanding of how miRNAs are expressed and function has been achieved, outstanding questions regarding the regulation of miRNA biogenesis and target recognition remain to be solved. In particular, the miRNA pathway has been shown to play an important role in diverse stress responses, but the mechanisms that control miRNA expression and activity under non-ideal conditions are poorly understood. Caenorhabditis elegans worms have proven to be an advantageous model to investigate miRNA biology at the organismal level. The development of sensitive biochemical methods, unique worm strains and robust computational pipelines has enabled novel insights into miRNA expression and targeting in the context of a developing animal. These approaches are now being utilized to understand how miRNAs contribute to the organismal response to heat stress. Additionally, dozens of novel long non-coding RNAs (lncRNAs) were found to be induced by heat shock and, already, one of them has been shown to promote survival during this stress. Thus, multiple ncRNA pathways potentially contribute to the changes in gene expression needed to survive this stress condition. The proposed research is focused on elucidating how the expression of specific miRNAs and lncRNAs is regulated by heat shock and, in turn, how these ncRNAs function to protect the organism during this stress. Over the next 5 years, these studies have the potential to reveal novel roles for ncRNAs in response to heat shock and set the stage for investigating the impact of ncRNA pathways in the organismal response to other stresses, including disease states. Work aimed at understanding how the 3' poly(A) tail on messenger RNAs (mRNAs) contributes to binding and regulation by the miRNA complex led to the surprising discovery that short poly(A) tails are commonly associated with highly expressed genes in somatic cells. Thus, a new research direction addresses previously unrecognized complexities in poly(A) tail length control and its relationship to the regulation of gene expression. The long-term goal of this research program is to contribute new insights into how ncRNAs and regulatory elements in mRNAs, such as poly(A) tails, control organismal gene expression under varied conditions. Furthermore, knowledge gained from these studies has the potential for significant impact on the design and utilization of RNA-based therapeutics for the treatment of human disease.