A role for RNA binding proteins in regulating lifespan has emerged. We identified a pair of neuronal RBPs, exc-7 and mbl-1, which display synthetic lifespan defects. Such a strong synthetic phenotype represented an opportunity to use transcriptomics to search for potential causative targets that are synthetically regulated. We identified a small handful of genes synthetically dysregulated in double mutants and systematically tested each candidate gene for functional contribution to the exc-7; mbl-1 lifespan phenotype. We identified one such gene, the ion transporter nhx-6, which is highly upregulated in double mutants. Overexpression of nhx-6 causes reduced lifespan, and deletion of nhx-6 in an exc-7; mbl-1 background partially restores both lifespan and healthspan. Together, these results reveal that a pair of RBPs mediate lifespan in part by inhibiting expression of an ion transporter, and provide a template for how synthetic phenotypes (including lifespan) can be dissected at the transcriptomic level to reveal potential causative genes. circRNAs are a rapidly developing area of research. We have developed a circRNA toolkit, including in vivo reporters with cell-specific resolution, as well as genetic methods for preventing the formation of endogenous circRNAs, to make important contributions to understanding the regulation and function of circRNAs in vivo. This toolkit can and is being used to study circRNA in general as well as in the context of aging.
Dr. Adam Norris
Biological Sciences, General, Cell Biology, Genetics, Life Sciences, Life Sciences, General/Other, Molecular Biology
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Napier-Jameson, Rebekah, "Regulation of mRNA and circRNA as a Cause and Consequence of Aging in Caenorhabditis elegans" (2023). Biological Sciences Theses and Dissertations. 22.
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