TY - JOUR
T1 - Retinal genomic fabric remodeling after optic nerve injury
AU - Victorino, Pedro Henrique
AU - Marra, Camila
AU - Iacobas, Dumitru Andrei
AU - Iacobas, Sanda
AU - Spray, David C.
AU - Linden, Rafael
AU - Adesse, Daniel
AU - Petrs‐silva, Hilda
N1 - Funding Information:
Funding: This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES) ‐ Finance Code 001; CNPq and FAPERJ. D.A.I. was supported by the Chancellorʹs Research Initiative (CRI) funding for the Center for Computational Systems Biology at the Prairie View A&M University. D.A. was supported by CNPq (grant numbers 44447878/2014‐ 0 and 401772/2015‐2) and by Fundação Oswaldo Cruz (Fiocruz) through the INOVA Fiocruz pro‐ gram, grant number 3231984391. D.C.S. was supported by National Institutes of Health grant num‐ ber NS092466.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - Complement cascade
KW - Genes coordination
KW - Glaucoma
KW - Microarray
KW - Notch signaling pathway
KW - Retinal ganglion cell degeneration
UR - http://www.scopus.com/inward/record.url?scp=85103084962&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103084962&partnerID=8YFLogxK
U2 - 10.3390/genes12030403
DO - 10.3390/genes12030403
M3 - Article
C2 - 33799827
AN - SCOPUS:85103084962
SN - 2073-4425
VL - 12
SP - 1
EP - 26
JO - Genes
JF - Genes
IS - 3
M1 - 403
ER -