Abstract
Purpose :
Complications of diabetic retinopathy (DR) were associated with a phenomenon called metabolic memory. The precise mechanisms governing metabolic memory are still poorly understood; however, emerging evidence indicates that persistent retinal mitochondrial dysfunction and sustained epigenetic alterations are pivotal in driving this phenomenon. Hence, we hypothesized that, identification of crucial transcription factors (TF) related to mitophagy and associated post transcriptional (m6A) modification would be a therapeutic target for DR.
Methods :
The NCBI-GEO (GSE60436) dataset was used to identify differentially expressed genes (DEGs). Mitophagy-related genes (MRGs) were retrieved from Genecard to find the common genes. Enrichr was employed to identify potential TFs which modulate the expression of MRGs and PPI network was built by Cytoscape. To resolve retinal heterogeneity and cell-specific expression of candidate genes, we have analyzed the single-cell RNA sequencing dataset (E-MTAB-9061) using Seurat (4.3.0). Finally, the RM2Target web server was utilized to identify post-transcriptional m6A modifications and its correlation.
Results :
We identified a distinct set of DEGs associated with DR, revealing 829 upregulated and 458 downregulated genes with 246 genes linked to mitophagy. Enrichr identified 124 TFs that potentiate to target MRGs. PPI study uncovered Ctnnb1, Myc, Esr1, Ar, Fos, Sp1, Nfkb1, Pou5f1, Smad2 and Nr3c1 as the top 10 crucial TFs and significant correlation was found between Ctnnb1 and Nr3c1. Further, single-cell RNA sequencing analysis identified endothelial cells, pericyte and pigment epithelial cells which were more prone to develop mitochondrial dysfunction as TFs were upregulated in these cell types. Additionally, RM2Target web server found different m6A modifier, which has positive correlation. These modifications might be essential for the post-transcriptional regulation of mitophagy-related crucial TFs related to DR and metabolic memory. However, further experimental validation may require to understand the impact of m6A modifiers on mitophagy-related TFs in DR.
Conclusions :
In summary, this study reported crucial epigenetically modified transcription factors and heterogeneity in retina which are associated with mitophagy in DR that provide a valuable insight for further research.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.