Article
Retinal Genomic Fabric Remodeling after Optic Nerve Injury
Registro en:
VICTORINO, Pedro Henrique et al. Retinal Genomic Fabric Remodeling after Optic Nerve Injury. Genes, v. 12, n. 3, 25 p, Mar. 2021.
2073-4425
10.3390/genes12030403
Autor
Victorino, Pedro Henrique
Marra, Camila
Iacobas, Dumitru Andrei
Iacobas, Sandra
Spray, David C.
Linden, Rafael
Adesse, Daniel
Petrs-Silva, Hida
Resumen
Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of
the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for
neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks
after optic nerve crush (ONC) and analyzed the data from the genomic fabric paradigm (GFP) to
bring additional insights into the molecular mechanisms of the retinal remodeling after induction of
RGC degeneration. GFP considers three independent characteristics for the expression of each gene:
level, variability, and correlation with each other gene. Thus, the 17,657 quantified genes in our study
generated a total of 155,911,310 values to analyze. This represents 8830x more data per condition
than a traditional transcriptomic analysis. ONC led to a 57% reduction in RGC numbers as detected
by retrograde labeling with 1,10
-dioctadecyl-3,3,3,30
-tetramethylindocarbocyanine perchlorate (DiI).
We observed a higher relative expression variability after ONC. Gene expression stability was
used as a measure of transcription control and disclosed a robust reduction in the number of very
stably expressed genes. Predicted protein–protein interaction (PPI) analysis with STRING revealed
axon and neuron projection as mostly decreased processes, consistent with RGC degeneration.
Conversely, immune response PPIs were found among upregulated genes. Enrichment analysis
showed that complement cascade and Notch signaling pathway, as well as oxidative stress and kit
receptor pathway were affected after ONC. To expand our studies of altered molecular pathways, we
examined the pairwise coordination of gene expressions within each pathway and within the entire
transcriptome using Pearson correlations. ONC increased the number of synergistically coordinated
pairs of genes and the number of similar profiles mainly in complement cascade and Notch signaling
pathway. This deep bioinformatic study provided novel insights beyond the regulation of individual
gene expression and disclosed changes in the control of expression of complement cascade and Notch
signaling functional pathways that may be relevant for both RGC degeneration and remodeling of
the retinal tissue after ONC.