Biogenesis and Function of Regulatory RNAs

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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.