Wednesday, December 6, 2023
12/6/2023
Project Summary/Abstract Precise control of gene expression programs is critical to maintain cellular homeostasis and ensure normal animal development. Improper gene expression is associated with numerous human pathologies, highlighting the importance of regulated gene expression. microRNAs (miRNAs) are key regulators of eukaryotic gene expression. Although more than half of all human mRNAs are predicted targets of miRNAs, our understanding of how miRNA-meditated gene repression is achieved remains incomplete. A critical step of miRNA-dependent gene regulation is the processing of stem-loop miRNA precursors into double-stranded miRNA duplexes. Each miRNA duplex comprises two strands destined for different fates: one strand is loaded into an Argonaute effector protein to form the miRNA-induced silencing complex (miRISC), while the other strand is degraded. As either miRNA strand can be functional, the decision of which miRNA strand is loaded into Argonaute effectively determines the target repertoire of miRISC. Improper miRNA strand choice can have severe consequences, as alternative miRNA strand selection has been observed in numerous human diseases including atrial fibrillation, multiple sclerosis, and several cancers. The objective of this proposal is to investigate the regulatory mechanisms of miRNA strand selection in vivo using the genetically amenable C. elegans model system. I will establish the hierarchy of miRNA duplex intrinsic and extrinsic features towards the regulation of miRNA strand selection. My central hypothesis is that external regulatory factors can override nucleotide sequence cues to regulate miRNA strand selection in a ‘switch-like’ fashion. Overall, completion of this proposal will significantly expand our understanding of how miRNA strand selection is regulated in the complex context of a developing organism. These findings should provide fundamental insights necessary to understand how miRNA strand selection becomes disrupted in human disease.
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