Retinal Genomic Fabric Remodeling after Optic Nerve Injury

Abstract

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 1,1′-dioctadecyl-3,3,3,3′-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.

Theory and Applications of the (Cardio) Genomic Fabric Approach to Post-Ischemic and Hypoxia-Induced Heart Failure

“…As one may note in Figure 1 , the hypoxia not only changed the expression levels of the individual genes, but also their expression control and expression coordination in functional pathways. Substantial changes in the genes’ expression control and inter-coordination were constant findings in all previous GFP studies on diseases on samples collected from both humans [ 26 , 30 , 31 , 33 , 55 ] and animal models (e.g., [ 57 , 58 , 59 , 60 ]). We believe that such rich additional information could be instrumental in developing a personalized genomic medicine.…”

“…So far, the GFP power to characterize the organization of the transcriptome was successfully tested in several other studies on neurological diseases (e.g., [ 35 , 57 , 58 , 59 ]), pulmonary hypertension [ 60 ], and cancers [ 26 , 30 , 31 , 33 , 55 , 70 ]. GFP proved also its ability to characterize the transcriptomic networks linking ionic channels and transporters across the heart chambers [ 6 ] as well as different cell types in insert systems [ 75 ].…”

A Personalized Genomics Approach of the Prostate Cancer

“…AVE was used to identify up-/down regulated genes in the “A”, “B”, “C” regions with respect to “N” and the differentially expressed genes between pairs of cancer nodules. REV analysis identified the very stably expressed genes (low REVs), critical for the survival and proliferation of each cell phenotype, and the very unstably expressed genes, used by the cells as vectors of adaptation to the environmental fluctuations [ 54 ]. Moreover, quantification of tens of thousands of genes at a time from the same region provided for each gene extra 14.907 correlation coefficients (COR) with each other gene within one region and 3 × 14,908 correlations with all genes from each other region.…”

TWEAKing the Hippocampus: The Effects of TWEAK on the Genomic Fabric of the Hippocampus in a Neuropsychiatric Lupus Mouse Model

“…Relative Expression Variability (REV) among biological replicas shows how much cellular homeostatic mechanisms control the transcript abundance against environmental slight random fluctuations [28], and the noise associated with the stochastic nature of the chemical reactions involved in the gene transcription. Genes critical for cell survival, proliferation, and integration in the multicellular structures are under strict control, while control of genes ensuring cell adaptation to environmental fluctuation is much more lenient.…”