Biogenesis and Function of Regulatory RNAs

项目总结 在过去的十年中，数以千计的非编码RNA(NcRNAs)被发现为潜在的 基因表达的调节者。在这一群体中，microRNAs(MiRNAs)已成为必不可少的 转录后基因调节的介体和特定miRNA途径中的缺陷 与许多人类疾病有关。虽然对miRNAs是如何表达和 功能已经实现，关于miRNA生物发生和调控的突出问题 目标识别仍有待解决。特别是，miRNA途径已经被证明扮演着一个 在不同的应激反应中起重要作用，但控制miRNA表达和 人们对非理想条件下的活动知之甚少。秀丽隐杆线虫有 事实证明，这是在生物体水平上研究miRNA生物学的一个有利模型。这个 发展灵敏的生化方法、独特的蠕虫菌株和稳健的计算 管道使对miRNA表达和靶向的新见解成为可能 发育中的动物。这些方法现在正被用来理解miRNAs是如何做出贡献的 对机体对热应激的反应。此外，数十种新型的长非编码RNA (LncRNA)被发现是由热休克诱导的，其中一种已经被证明是 在这种压力下促进生存。因此，多个ncRNA通路可能有助于 在这种压力条件下生存所需的基因表达的变化。拟议的研究是 侧重于阐明特定的miRNAs和lncRNAs的表达是如何受热调节的 休克，反过来，这些ncRNA如何在这种压力下保护有机体。超过了 未来5年，这些研究有可能揭示ncRNAs在热反应中的新角色 休克并为研究ncRNA通路在生物反应中的影响奠定了基础 其他压力，包括疾病状态。旨在了解3‘聚(A)是如何尾随的工作 信使RNAs(MRNAs)有助于通过miRNA复合体结合和调节 令人惊讶的发现，短聚(A)尾巴通常与高表达的基因有关 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。长期目标 这项研究计划的目的是为ncRNA和调控元件如何在 RNA，如聚(A)尾，在不同的条件下控制着生物基因的表达。 此外，从这些研究中获得的知识有可能对 以RNA为基础的治疗人类疾病的疗法的设计和应用。

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.