Genetic regulators of stress-induced RNA mis-splicing in Caenorhabditis elegans
Date
2021-09-29
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0003-4800-2286
Type
Thesis
Degree Level
Masters
Abstract
Splicing of pre-mRNA is an essential process for all eukaryotic dividing cells. Pre-mRNA splicing defects are implicated in numerous human diseases, including Alzheimer’s disease and cancer, however its cause is poorly understood. Using the nematode Caenorhabditis elegans as a model, the Wu lab has recently shown that exposure to the environmental heavy metal cadmium can cause RNA splicing disruption, implicating loss of RNA metabolism regulation as a potential mechanism of cadmium toxicity. To understand the genetic mechanism of RNA splicing regulation under environmental stress, I sought to identify and characterize genes that, when knocked down, can protect against RNA splicing errors. Using a C. elegans in vivo splicing reporter, I found that an overwhelming majority of the gene knock-downs that improved RNA splicing under stress encode various components of the translation machinery, including ifg-1, which encodes the human eIF4G gene previously shown to regulate aging. Knockdown of various protein translation related genes has been shown to not only increase C. elegans lifespan but now also to enhance resistance to cadmium survival. Using RNA-sequencing, I found that ifg-1 partial loss of function mutants show increases in expression of >80 genes that regulate RNA splicing; importantly, ifg-1 mutants exposed to cadmium show a 50% decrease in cadmium-induced alternative splicing events observed in wild-type worms. Downstream of ifg-1, I have identified the SMA family of transcription factors as key regulators that are required for RNA splicing protection under stress in the ifg-1 mutants. Suppression of translation has previously been shown to be beneficial in promoting longevity and stress resistance in various organisms including C. elegans, and my study may have implicated a novel mechanism through which these physiological benefits are achieved in part by improvements to RNA splicing fidelity.
Description
Keywords
RNA splicing, Caenorhabditis elegans, neurodegenerative disease, aging, cadmium, ifg-1
Citation
Degree
Master of Science (M.Sc.)
Department
Veterinary Biomedical Sciences
Program
Veterinary Biomedical Sciences