A causal mediation model of ischemia reperfusion injury in the retina

Abstract

The goal of this study is to develop a model that explains the relationship between microRNAs, transcription factors, and their co-target genes. This relationship was previously reported in gene regulatory loops associated with 24 hour (24h) and 7 day (7d) time periods following ischemia-reperfusion injury in a rat’s retina. Using a model system of retinal ischemia-reperfusion injury, we propose that microRNAs first influence transcription factors, which in turn act as mediators to influence transcription of genes via triadic regulatory loops. Analysis of the relative contributions of direct and indirect regulatory influences on genes revealed that a substantial fraction of the regulatory loops (69% for 24 hours and 77% for 7 days) could be explained by causal mediation. Over 40% of the mediated loops in both time points were regulated by transcription factors only, while about 20% of the loops were regulated entirely by microRNAs. The remaining fractions of the mediated regulatory loops were cooperatively mediated by both microRNAs and transcription factors. The results from these analyses were supported by the patterns of expression of the genes, transcription factors, and microRNAs involved in the mediated loops in both post-ischemic time points. Additionally, network motif detection for the mediated loops showed a handful of time specific motifs related to ischemia-reperfusion injury in a rat’s retina. In summary, the effects of microRNAs on genes are mediated, in large part, via transcription factors.

Polygenic Risk Score Improves Cataract Prediction in East Asian Population

“…The sec1 family domain (SCFD2) gene, identified in the older group, is a protein-coding gene that participates in protein transport and exocytosis [ 40 ] and is involved in multiple personality disorders. In terms of its potential role in ophthalmic diseases, a previous study has found the opposite effect of the Scfd2 gene on STAT1 and miR-493 regulators, which are associated with ischemia, a type of common pathological pathway for neuronal cell degeneration associated with many retinal diseases [ 41 , 42 ]. Other results from GWAS analysis also indicated that several variants within the SCFD2 gene locus achieved genome-wide statistical significance in their association with cataracts in the Australian Shepherd breed of domestic dogs [ 43 ].…”

Whole-eye transplantation: Current challenges and future perspectives

“…Maintaining the viability of the donor eye post-enucleation stands as a paramount challenge in whole-eye transplantation, underpinned by three critical parameters: The recovery of visual function post-transplant, the resilience of the outer retina to ischemia, and the survival of RGCs[ 33 , 82 , 83 ]. The journey toward understanding and optimizing these factors reveals a complex interplay of biological and technical considerations.…”