Circular RNAs profiling in the cystathionine-ß-synthase mutant mouse reveals novel gene targets for hyperhomocysteinemia induced ocular disorders.

ABSTRACT

Cystathionine-ß-synthase (CBS) gene encodes L-serine hydrolyase which catalyzes ß-reaction to condense serine with homocysteine (Hcy) by pyridoxal-5'-phosphate helps to form cystathionine which in turn is converted to cysteine. CBS resides at the intersection of transmethylation, transsulfuration, and remethylation pathways, thus lack of CBS fundamentally blocks Hcy degradation; an essential step in glutathione synthesis. Redox homeostasis, free-radical detoxification and one-carbon metabolism (Methionine-Hcy-Folate cycle) require CBS and its deficiency leads to hyperhomocysteinemia (HHcy) causing retinovascular thromboembolism and eye-lens dislocation along with vascular cognitive impairment and dementia. HHcy results in retinovascular, coronary, cerebral and peripheral vessels' dysfunction and how it causes metabolic dysregulation predisposing patients to serious eye conditions remains unknown. HHcy orchestrates inflammation and redox imbalance via epigenetic remodeling leading to neurovascular pathologies. Although circular RNAs (circRNAs) are dominant players regulating their parental genes' expression dynamics, their importance in ocular biology has not been appreciated. Progress in gene-centered analytics via improved microarray and bioinformatics are enabling dissection of genomic pathways however there is an acute under-representation of circular RNAs in ocular disorders. This study undertook circRNAs' analysis in the eyes of CBS deficient mice identifying a pool of 12532 circRNAs, 74 exhibited differential expression profile, ∼27% were down-regulated while most were up-regulated (∼73%). Findings also revealed several microRNAs that are specific to each circRNA suggesting their roles in HHcy induced ocular disorders. Further analysis of circRNAs helped identify novel parental genes that seem to influence certain eye disease phenotypes.