scholarly journals Comprehensive analysis of gene expression in human retina and supporting tissues

2014 ◽  
Vol 23 (15) ◽  
pp. 4001-4014 ◽  
Author(s):  
Mingyao Li ◽  
Cheng Jia ◽  
Krista L. Kazmierkiewicz ◽  
Anita S. Bowman ◽  
Lifeng Tian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Phenotypic Diversity ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Posterior Part ◽  
Age Related Macular Degeneration ◽  
Human Retina ◽  
Significant Differential Expression ◽  
Age Related

Understanding the influence of gene expression on the molecular mechanisms underpinning human phenotypic diversity is fundamental to being able to predict health outcomes and treat disease. We have carried out whole transcriptome expression analysis on a series of eight normal human postmortem eyes by RNA sequencing. Here we present data showing that ∼80% of the transcriptome is expressed in the posterior layers of the eye and that there is significant differential expression not only between the layers of the posterior part of the eye but also between locations of a tissue layer. These differences in expression also extend to alternative splicing and splicing factors. Differentially expressed genes are enriched for genes associated with psychiatric, immune and cardiovascular disorders. Enrichment categories for gene ontology included ion transport, synaptic transmission and visual and sensory perception. Lastly, allele-specific expression was found to be significant forCFH,C3 andCFB, which are known risk genes for age-related macular degeneration. These expression differences should be useful in determining the underlying biology of associations with common diseases of the human retina, retinal pigment epithelium and choroid and in guiding the analysis of the genomic regions involved in the control of normal gene expression.

scholarly journals CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Saumil Sethna ◽  
Patrick A. Scott ◽  
Arnaud P. J. Giese ◽  
Todd Duncan ◽  
Xiaoying Jian ◽  
...  
Keyword(s):  
Visual Function ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Negative Regulator ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Mtorc1 Signaling ◽  
Marked Accumulation

AbstractAge-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling—a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.

scholarly journals Embryonic stem cell microenvironment enhances proliferation of human retinal pigment epithelium cells by activating the PI3K signaling pathway

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jiahui Liu ◽  
Liu Yang ◽  
Xiaoran Wang ◽  
Shoubi Wang ◽  
Zheqian Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Signaling Pathway ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Embryonic Stem ◽  
Age Related Macular Degeneration ◽  
Pi3k Signaling ◽  
Age Related ◽  
Pi3k Signaling Pathway

Abstract Background Retinal pigment epithelium (RPE) replacement has been proposed as an efficacious treatment for age-related macular degeneration (AMD), which is the primary cause of vision loss in the elderly worldwide. The embryonic stem cell (ESC) microenvironment has been demonstrated to enable mature cells to gain a powerful proliferative ability and even enhance the stem/progenitor phenotype via activation of the phosphoinositide 3-kinase (PI3K) signaling pathway. As the PI3K signaling pathway plays a pivotal role in proliferation and homeostasis of RPE, we hypothesize that the stemness and proliferative capability of RPE can be enhanced by the ESC microenvironment via activation of the PI3K signaling pathway. Methods To investigate whether the ESC microenvironment improves the stem cell phenotype and proliferation properties of human RPE (hRPE) cells by regulating the PI3K signaling pathway, primary hRPE cells were cocultured with either ESCs or human corneal epithelial cells (CECs) for 72 h, after which their proliferation, apoptosis, cell cycle progression, and colony formation were assayed to evaluate changes in their biological characteristics. Gene expression was detected by real-time PCR and protein levels were determined by western blotting or immunofluorescence. LY294002, an antagonist of the PI3K signaling pathway, was used to further confirm the mechanism involved. Results In comparison to hRPE cells cultured alone, hRPE cells cocultured with ESCs had an increased proliferative capacity, reduced apoptotic rate, and higher colony-forming efficiency. The expression of the stem cell-associated marker KLF4 and the differentiation marker CRALBP increased and decreased, respectively, in hRPE cells isolated from the ESC coculture. Furthermore, PI3K pathway-related genes were significantly upregulated in hRPE cells after exposure to ESCs. LY294002 reversed the pro-proliferative effect of ESCs on hRPE cells. In contrast, CECs did not share the ability of ESCs to influence the biological behavior and gene expression of hRPE cells. Conclusions Our findings indicate that the ESC microenvironment enhances stemness and proliferation of hRPE cells, partially via activation of the PI3K signaling pathway. This study may have a significant impact and clinical implication on cell therapy in regenerative medicine, specifically for age-related macular degeneration.

scholarly journals Human iPSC-derived retinal pigment epithelium: a model system for identifying and functionally characterizing causal variants at AMD risk loci

2018 ◽  
Author(s):  
Erin N. Smith ◽  
Agnieszka D’Antonio-Chronowska ◽  
William W. Greenwald ◽  
Victor Borja ◽  
Lana R. Aguiar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Induced Pluripotent Stem Cell ◽  
Age Related Macular Degeneration ◽  
Molecular Characteristics ◽  
Specific Expression ◽  
Age Related ◽  
Causal Variants

SummaryWe evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observe high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal-RPE. We performed fine-mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele specific expression of a non-coding transcript. These results provide insight into the mechanism underlying the association of the VEGFA locus with AMD.

scholarly journals Systems Biology Profiling of AMD on the Basis of Gene Expression

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Mones S. Abu-Asab ◽  
Jose Salazar ◽  
Jingsheng Tuo ◽  
Chi-Chao Chan
Keyword(s):  
Gene Expression ◽  
Systems Biology ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Disease Spectrum ◽  
Age Related ◽  
Dry Amd ◽  
Pathway Networks

Genetic pathways underlying the initiation and progression of age-related macular degeneration (AMD) have not been yet sufficiently revealed, and the correlations of AMD’s genotypes, phenotypes, and disease spectrum are still awaiting resolution. We are tackling both problems with systems biology phylogenetic parsimony analysis. Gene expression data (GSE29801: NCBI, Geo) of macular and extramacular specimens of the retinas and retinal pigment epithelium (RPE) choroid complexes representing dry AMD without geographic atrophy (GA), choroidal neovascularization (CNV), GA, as well as pre-AMD and subclinical pre-AMD were polarized against their respective normal specimens and then processed through the parsimony program MIX to produce phylogenetic cladograms. Gene lists from cladograms’ nodes were processed in Genomatix GePS to reveal the affected signaling pathway networks. Cladograms exposed a highly heterogeneous transcriptomic profiles within all the conventional phenotypes. Moreover, clades and nodal synapomorphies did not support the classical AMD phenotypes as valid transcriptomal genotypes. Gene lists defined by cladogram nodes showed that the AMD-related deregulations occurring in the neural retina were different from those in RPE-choroidal tissue. Our analysis suggests a more complex transcriptional profile of the phenotypes than expected. Evaluation of the disease in much earlier stages is needed to elucidate the initial events of AMD.

scholarly journals PTEN Reduced UVB-Mediated Apoptosis in Retinal Pigment Epithelium Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Jia He ◽  
Chongde Long ◽  
Zixin Huang ◽  
Xin Zhou ◽  
Xielan Kuang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Molecular Mechanisms ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Rpe Cells ◽  
Age Related ◽  
Induced Apoptosis

Age-related macular degeneration (AMD) is a leading cause of blindness and progressive loss of central vision in the elderly population. The important factor of AMD pathogenesis is the degeneration of retinal pigment epithelial (RPE) cells by oxidative stress. Inactivation of PTEN can disrupt intercellular adhesion in the RPE cells, but the mechanism of oxidative stress is less known. Here we presented evidence that UVB-mediated oxidative stress induced apoptosis in ARPE-19 cells. Downregulation of the expression of PTEN in UVB-irradiative RPE cells triggered DNA damage and increased the level of UVB-induced apoptosis by activating p53-dependent pathway. However, overexpression of PTEN increased cell survival by suppressing p-H2A in response to DNA damage and apoptosis. When using Pifithrin-α(one of p53 inhibitors), the level of p53-dependent apoptosis was significantly lower than untreated, which suggested that p53 was possibly involved in PTEN-dependent apoptosis. Thus, it elucidated the molecular mechanisms of UVB-induced damage in RPE cells and may offer an alternative therapeutic target in dry AMD.

scholarly journals Interplay between Autophagy and the Ubiquitin-Proteasome System and Its Role in the Pathogenesis of Age-Related Macular Degeneration

2019 ◽  
Vol 20 (1) ◽  
pp. 210 ◽  
Author(s):  
Janusz Blasiak ◽  
Elzbieta Pawlowska ◽  
Joanna Szczepanska ◽  
Kai Kaarniranta
Keyword(s):  
Waste Management ◽  
Macular Degeneration ◽  
Molecular Mechanisms ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Ubiquitin Proteasome System ◽  
Age Related Macular Degeneration ◽  
E3 Ligases ◽  
Age Related ◽  
Ubiquitin Proteasome

Age-related macular degeneration (AMD) is a complex eye disease with many pathogenesis factors, including defective cellular waste management in retinal pigment epithelium (RPE). Main cellular waste in AMD are: all-trans retinal, drusen and lipofuscin, containing unfolded, damaged and unneeded proteins, which are degraded and recycled in RPE cells by two main machineries—the ubiquitin-proteasome system (UPS) and autophagy. Recent findings show that these systems can act together with a significant role of the EI24 (etoposide-induced protein 2.4 homolog) ubiquitin ligase in their action. On the other hand, E3 ligases are essential in both systems, but E3 is degraded by autophagy. The interplay between UPS and autophagy was targeted in several diseases, including Alzheimer disease. Therefore, cellular waste clearing in AMD should be considered in the context of such interplay rather than either of these systems singly. Aging and oxidative stress, two major AMD risk factors, reduce both UPS and autophagy. In conclusion, molecular mechanisms of UPS and autophagy can be considered as a target in AMD prevention and therapeutic perspective. Further work is needed to identify molecules and effects important for the coordination of action of these two cellular waste management systems.

scholarly journals Embryonic stem cell microenvironment enhances proliferation of human retinal pigment epithelium cells by activating the PI3K signaling pathway

2020 ◽  
Author(s):  
Jiahui Liu ◽  
Liu Yang ◽  
Xiaoran Wang ◽  
Shoubi Wang ◽  
Zheqian Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Signaling Pathway ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Embryonic Stem ◽  
Age Related Macular Degeneration ◽  
Pi3k Signaling ◽  
Age Related ◽  
Pi3k Signaling Pathway

Abstract Background: Retinal pigment epithelium (RPE) replacement has been proposed as an efficacious treatment for Age-related macular degeneration (AMD), which is the primary causes of vision loss in the elderly worldwide. The embryonic stem cell (ESC) microenvironment has been demonstrated to enable mature cells to gain a powerful proliferative ability and even enhance the stem/progenitor phenotype via activation of the phosphoinositide 3-kinase (PI3K) signaling pathway. As the PI3K signaling pathway plays a pivotal role in proliferation and homeostasis of RPE, we hypothesize that the stemness and proliferative capability of RPE can be enhanced by the ESC microenvironment via activation of the PI3K signaling pathway.Methods: To investigate whether the ESC microenvironment improves the stem cell phenotype and proliferation properties of human RPE (hRPE) cells by regulating the PI3K signaling pathway, primary hRPE cells were cocultured with either ESCs or human corneal epithelial cells (CECs) for 72 hours, after which their proliferation, apoptosis, cell cycle progression, and colony formation were assayed to evaluate changes in their biological characteristics. Gene expression was detected by real-time PCR and protein levels were determined by western blotting or immunofluorescence. LY294002, an antagonist of the PI3K signaling pathway, was used to further confirm the mechanism involved.Results: In comparison to hRPE cells cultured alone, hRPE cells cocultured with ESCs had an increased proliferative capacity, reduced apoptotic rate, and higher colony-forming efficiency. The expression of the stem cell-associated marker KLF4 and the differentiation marker CRALBP increased and decreased, respectively, in hRPE cells isolated from the ESC coculture. Furthermore, PI3K pathway-related genes were significantly up-regulated in hRPE cells after exposure to ESCs. LY294002 reversed the pro-proliferative effect of ESCs on hRPE cells. In contrast, CECs did not share the ability of ESCs to influence the biological behavior and gene expression of hRPE cells.Conclusions: Our findings indicate that the ESC microenvironment enhances stemness and proliferation of hRPE cells, partially via activation of the PI3K signaling pathway. This study may have a significant impact and clinical implication on cell therapy in regenerative medicine, specifically for age-related macular degeneration.

scholarly journals Ocular disease mechanisms elucidated by genetics of human fetal retinal pigment epithelium gene expression

2018 ◽  
Author(s):  
Boxiang Liu ◽  
Melissa A. Calton ◽  
Nathan S. Abell ◽  
Gillie Benchorin ◽  
Michael J. Gloudemans ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinal Pigment Epithelium ◽  
Large Scale ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Lipid Synthesis ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Metabolic Conditions ◽  
Association Data

AbstractThe eye is an intricate organ with limited representation in large-scale functional genomics datasets. The retinal pigment epithelium (RPE) serves vital roles in ocular development and retinal homeostasis. We interrogated the genetics of gene expression of cultured human fetal RPE (fRPE) cells under two metabolic conditions. Genes with disproportionately high fRPE expression are enriched for genes related to inherited ocular diseases. Variants near these fRPE-selective genes explain a larger fraction of risk for both age-related macular degeneration (AMD) and myopia than variants near genes enriched in 53 other human tissues. Increased mitochondrial oxidation of glutamine by fRPE promoted expression of lipid synthesis genes implicated in AMD. Expression and splice quantitative trait loci (e/sQTL) analysis revealed shared and metabolic condition-specific loci of each type and several eQTL not previously described in any tissue. Fine mapping of fRPE e/sQTL across AMD and myopia genome-wide association data suggests new candidate genes, and mechanisms by which the same common variant of RDH5 contributes to both increased AMD risk and decreased myopia risk. Our study highlights the unique transcriptomic characteristics of fRPE and provides a resource to connect e/sQTL in a critical ocular cell type to monogenic and complex eye disorders.

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