Talk abstracts
Talk on Thursday 03:15-03:30pm submitted by Electra Coffman
Identifying the ferroptosis pathway in an age-dependent cortical cataract model transcriptome
Electra Coffman (Molecular, Cellular, and Developmental Biology Graduate Program), Timothy Plageman Jr. (College of Optometry, The Ohio State University)
Abstract:
Cataracts, an ocular disease marked by the opacification of the lens, are the global leading cause of blindness in the world. The two most common types of cataracts are nuclear (central) and cortical (circumferential). Although the molecular causes of age-dependent nuclear cataracts have been well studied, the etiology of cortical cataracts remains ambiguous. We previously established that mice lacking a cell adhesion gene, Arvcf, develop premature cortical cataracts with clinical-like spoking by 5 months of age and have severely disturbed adherens junctions as soon as 30 days. We hypothesize that this disruption in cell adhesion leads to indirect transcriptomic and cell signaling pathway changes that contribute to cortical cataracts. To test this, we used transcriptome analysis methods. As Arvcf has yet to be shown to localize to lens cell nuclei, we first performed RT-PCR to reveal that the lens-specific Arvcf transcript variant indeed lacks the canonical nuclear localization sequence. To then identify possible indirect pathways of an Arvcf-regulated lens transcriptome, lens fibers from 35-day-old mice with or without Arvcf were analyzed by bulk RNA sequencing. GO enrichment for biological processes and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was then used to analyze differentially expressed genes. Surprisingly, we identified cell death and ferroptosis as the most highly enriched pathways. Genes associated with ferroptosis, an iron-dependent regulated cell death mechanism, were severely altered in Arvcf-deficient lenses. Iron export and storage genes were upregulated while heme catalysis genes were downregulated, implicating intracellular iron overload as a key step in cortical cataract development. Here, we reveal the ferroptosis pathway as intermediate advancement toward lens cortical cataracts. We further demonstrate the first transcriptomic dataset in an age-dependent cortical cataract model to outline this diseases mechanistic progression.
Keywords: Cataracts, Ferroptosis, RNAseq