Whole-genome methylation profiling of the retinal pigment epithelium of individuals with age-related macular degeneration reveals differential methylation of the SKI, GTF2H4, and TNXB genes

Porter, Louise F.; Saptarshi, Neil; Fang, Yongxiang; Rathi, Sonika; Hollander, Anneke I. den; Clark, Simon J.; Bishop, Paul; Olsen, Timothy W.; Liloglou, Triantafillos; Chavali, Venkata R M; Paraoan, Luminita

doi:10.1186/s13148-019-0608-2

Cited by 44 publications

(60 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among these are oxidative and nitrosative stress associated with smoking, light exposure/phototoxicity, and impaired phagocytosis . Epigenetic modifications have also been implicated in AMD pathophysiology …”

Section: Introductionmentioning

confidence: 99%

“…[4][5][6][7][8][9][10][11] Epigenetic modifications have also been implicated in AMD pathophysiology. [12][13][14][15][16] Aging causes morphological changes in Bruch's membrane, including calcification and fragmentation due to the sub-RPE deposits of drusen that are associated with macular degeneration. 3,17 Nonenzymatic nitrosylation due to smoking affects the properties of Bruch's membrane by cross-linking collagens in all layers of the structure.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions

Gong

Cai

Noggle

et al. 2019

Stem Cells Translational Medicine

View full text Add to dashboard Cite

Modeling age‐related macular degeneration (AMD) is challenging, because it is a multifactorial disease. To focus on interactions between the retinal pigment epithelium (RPE) and Bruch's membrane, we generated RPE from AMD patients and used an altered extracellular matrix (ECM) that models aged Bruch's membrane. Induced pluripotent stem cells (iPSCs) were generated from fibroblasts isolated from AMD patients or age‐matched (normal) controls. RPE derived from iPSCs were analyzed by morphology, marker expression, transepithelial electrical resistance (TER), and phagocytosis of rod photoreceptor outer segments. Cell attachment and viability was tested on nitrite‐modified ECM, a typical modification of aged Bruch's membrane. DNA microarrays with hierarchical clustering and analysis of mitochondrial function were used to elucidate possible mechanisms for the observed phenotypes. Differentiated RPE displayed cell‐specific morphology and markers. The TER and phagocytic capacity were similar among iPSC‐derived RPE cultures. However, distinct clusters were found for the transcriptomes of AMD and control iPSC‐derived RPE. AMD‐derived iPSC‐RPE downregulated genes responsible for metabolic‐related pathways and cell attachment. AMD‐derived iPSC‐RPE exhibited reduced mitochondrial respiration and ability to attach and survive on nitrite‐modified ECM. Cells that did attach induced the expression of complement genes. Despite reprogramming, iPSC derived from AMD patients yielded RPE with a transcriptome that is distinct from that of age‐matched controls. When challenged with an AMD‐like modification of Bruch's membrane, AMD‐derived iPSC‐RPE activated the complement immune system.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions

Gong

Cai

Noggle

et al. 2019

Stem Cells Translational Medicine

View full text Add to dashboard Cite

show abstract

“…Mercury is found in retinal pigment epithelial cells [19,29,56,57] and so may play a part in the pathogenesis of macular degeneration. In macular degeneration, free radical formation [58] and epigenetic variations [59], both toxic actions of mercury, have been postulated to underlie retinal damage. The mouse eye does not have a well-developed macula [60,61] and so is not an ideal model to study macular degeneration, but peripapillary atrophy and disruption of the retinal pigment epithelium are two features of macular degeneration [50,51] that could be explained by the uptake of mercury by the retinal pigment epithelium.…”

Section: Discussionmentioning

confidence: 99%

Mercury in the retina and optic nerve following prenatal exposure to mercury vapor

2019

View full text Add to dashboard Cite

Damage to the retina and optic nerve is found in some neurodegenerative disorders, but it is unclear whether the optic pathway and central nervous system (CNS) are affected by the same injurious agent, or whether optic pathway damage is due to retrograde degeneration following the CNS damage. Finding an environmental agent that could be responsible for the optic pathway damage would support the hypothesis that this environmental toxicant also triggers the CNS lesions. Toxic metals have been implicated in neurodegenerative disorders, and mercury has been found in the retina and optic nerve of experimentally-exposed animals. Therefore, to see if mercury exposure in the prenatal period could be one link between optic pathway damage and human CNS disorders of later life, we examined the retina and optic nerve of neonatal mice that had been exposed prenatally to mercury vapor, using a technique, autometallography, that detects the presence of mercury within cells. Pregnant mice were exposed to a non-toxic dose of mercury vapor for four hours a day for five days in late gestation, when the mouse placenta most closely resembles the human placenta. The neonatal offspring were sacrificed one day after birth and gapless serial sections of formalin-fixed paraffin-embedded blocks containing the eyes were stained with silver nitrate autometallography to detect inorganic mercury. Mercury was seen in the nuclear membranes of retinal ganglion cells and endothelial cells. A smaller amount of mercury was present in the retinal inner plexiform and inner nuclear layers. Mercury was conspicuous in the peripapillary retinal pigment epithelium. In the optic nerve, mercury was seen in the nuclear membranes and processes of glia and in endothelial cells. Optic pathway and CNS endothelial cells contained mercury. In conclusion, mercury is taken up preferentially by fetal retinal ganglion cells, optic nerve glial cells, the retinal pigment epithelium, and endothelial cells. Mercury induces free radical formation, autoimmunity, and genetic and epigenetic changes, so these findings raise the possibility that mercury plays a part in the pathogenesis of degenerative CNS disorders that also affect the retina and optic nerve.

show abstract

“…A large dataset consisting of 1,28,175 retinal images is used and trained using deep CNN. In [28] data augmentation method is used to generate the data on CNN architecture. Fuzzy models are used in [29], a hybrid model that is designed based on fuzzy logic, Hough Transform and numerous extraction methods are being implemented as part of their system.…”

Section: Related Workmentioning

confidence: 99%

Blended Multi-Modal Deep ConvNet Features for Diabetic Retinopathy Severity Prediction

et al. 2020

View full text Add to dashboard Cite

Diabetic Retinopathy (DR) is one of the major causes of visual impairment and blindness across the world. It is usually found in patients who suffer from diabetes for a long period. Major focus of this work is to derive optimal representation of retinal images that further helps to improve the performance of DR recognition models. In order to extract optimal representation, features extracted from multiple pre-trained ConvNet models are blended using proposed multi-modal fusion module. These final representations are used to train a Deep Neural Network (DNN) used for DR identification and severity level prediction. As each ConvNet extract different features, fusing them using 1-D pooling, and cross pooling lead to better representation than using features extracted from a single ConvNet. Experimental studies on benchmark Kaggle APTOS 2019 contest dataset reveals that the model trained on proposed blended feature representations is superior to the existing methods. In addition, we notice that cross average pooling based fusion of features from Xception and VGG16 is the most appropriate for DR recognition. With the proposed model, we achieve an accuracy of 97.41%, and a kappa statistic of 94.82 for DR identification and an accuracy of 81.7% and a kappa statistic of 71.1% for severity level prediction. Another interesting observation is that, DNN with dropout at input layer converges faster when trained using blended features, than compared to the same model trained using uni-modal deep features.

show abstract

Whole-genome methylation profiling of the retinal pigment epithelium of individuals with age-related macular degeneration reveals differential methylation of the SKI, GTF2H4, and TNXB genes

Cited by 44 publications

References 54 publications

Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions

Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions

Mercury in the retina and optic nerve following prenatal exposure to mercury vapor

Blended Multi-Modal Deep ConvNet Features for Diabetic Retinopathy Severity Prediction

Contact Info

Product

Resources

About