Epigenetic Mechanisms of the Aging Human Retina

Abstract

Degenerative retinal diseases, such as glaucoma, age-related macular degeneration, and diabetic retinopathy, have complex etiologies with environmental, genetic, and epigenetic contributions to disease pathology. Much effort has gone into elucidating both the genetic and the environmental risk factors for these retinal diseases. However, little is known about how these genetic and environmental risk factors bring about molecular changes that lead to pathology. Epigenetic mechanisms have received extensive attention of late for their promise of bridging the gap between environmental exposures and disease development via their influence on gene expression. Recent studies have identified epigenetic changes that associate with the incidence and/or progression of each of these retinal diseases. Therefore, these epigenetic modifications may be involved in the underlying pathological mechanisms leading to blindness. Further genome-wide epigenetic studies that incorporate well-characterized tissue samples, consider challenges similar to those relevant to gene expression studies, and combine the genome-wide epigenetic data with genome-wide genetic and expression data to identify additional potentially causative agents of disease are needed. Such studies will allow researchers to create much-needed therapeutics to prevent and/or intervene in disease progression. Improved therapeutics will greatly enhance the quality of life and reduce the burden of disease management for millions of patients living with these potentially blinding conditions.

Keywords: DNA methylation; age-related macular degeneration; aging; chromatin; diabetic retinopathy; epigenetics; genome-wide; glaucoma; histone modification; neurodegeneration.

Figure 1

Chromatin modifications affect gene expression. Changes in epigenetic marks, such as DNA methylation and histone modifications, each contribute to the regulation of gene expression. DNA methylation in the promoter regions of genes is generally associated with decreased gene expression. Histone modifications can be either activating or repressive. Histone acetylation and phosphorylation are generally associated with active genes; histone methylation and ubiquitination arrangements are associated with either active or repressed genes.

Figure 2

Epigenetics in aging and age-related disease. Stable epigenetic marks may be the link between genetic and environmental processes involved in the development of age-related diseases, such as AMD. Environmental influences contribute to epigenetic changes that accumulate with age. Risk factors, such as diet, obesity, smoking, sun exposure, and age, may elicit epigenetic changes that accumulate over a lifetime, eventually resulting in altered expression of genes involved in the disease process. These environmental influences contribute to epigenetic modifications, such as DNA methylation (green ovals), histone methylation (purple pentagons), histone acetylation (orange pentagons), histone ubiquitination (blue pentagons), and histone phosphorylation (red pentagons). The epigenetic changes that accumulate throughout the genome may associate with transcriptional changes at the affected genomic loci. Such expression changes at disease-relevant loci may promote either protection against or progression of age-related disease. The sum of these effects over time may then perturb the normal, healthy homeostasis enough to result in the development and/or progression of diseases such as AMD.

Figure 3

Progression of retinal disease. (A) Fundus and OCT images of normal eye with anatomy labels. (B) Fundus image of an eye with glaucoma. Note the optic nerve damage. (C) Fundus images of normal, intermediate, and advanced (GA and neovascular) AMD. Note the drusen deposits, atrophy, and neovascularization. (D) Fundus image of an eye with DR. Note the abnormal blood vessels and hard exudates. Photographs taken from DeAngelis laboratory patient cohorts. The study protocol was reviewed and approved by the Institutional Review Board at the University of Utah and conforms to the tenets of the Declaration of Helsinki.

Figure 3

Progression of retinal disease. (A) Fundus and OCT images of normal eye with anatomy labels. (B) Fundus image of an eye with glaucoma. Note the optic nerve damage. (C) Fundus images of normal, intermediate, and advanced (GA and neovascular) AMD. Note the drusen deposits, atrophy, and neovascularization. (D) Fundus image of an eye with DR. Note the abnormal blood vessels and hard exudates. Photographs taken from DeAngelis laboratory patient cohorts. The study protocol was reviewed and approved by the Institutional Review Board at the University of Utah and conforms to the tenets of the Declaration of Helsinki.

Figure 4

Siblings extremely discordant for AMD. These fundus images illustrate the retinas of discordant siblings with identical risk profiles for major AMD genetic loci, smoking, BMI, and CVD. Note the severe neovascular AMD in one sibling and normal macula in the other at a comparable age. Environmentally induced epigenetic changes may explain the occurrence of such discordance for AMD or other age-related disease. OD, oculus dexter (right eye); OS, oculus sinister (left eye). Photographs taken from DeAngelis laboratory patient cohorts. The study protocol was reviewed and approved by the Institutional Review Board at the University of Utah and conforms to the tenets of the Declaration of Helsinki.

Figure 5

Why do some patients progress beyond and others stop at an intermediate stage of disease? The complex functional networks at play within a cell or tissue are likely susceptible to small perturbations exerted by environmental influences over long periods of time. The gradual accumulation of altered expression or function of key factors within a system may then lead to dysfunction and disease. Disease-promoting factors (such as smoking, obesity, and poor diet) work to alter the networks in ways that lead to pathological states, whereas disease-preventing factors (such as antioxidant consumption and healthy BMI) oppose the progression of disease by keeping the system within the bounds of healthy function. The ratio of disease-promoting and -preventing influences may balance at different equilibrium points, leading to individual cases that progress only so far along the pathological pathway before reaching that balance point. By discovering the various promoting and preventing factors, along with their respective significances at each point along the disease progression timeline, researchers (and eventually clinicians and patients) will be able to balance the networks to prevent or reverse the progression of disease. Photographs taken from the DeAngelis laboratory cohorts. The study protocol was reviewed and approved by the Institutional Review Board at the University of Utah and conforms to the tenets of the Declaration of Helsinki.

Figure 6

Ideal experimental setup for genome-wide epigenetic experiments. Each of these nine characteristics contributes to the production of meaningful epigenetic data that can be used to identify genes that are differentially methylated/modified in specific disease states. The combination of robust epigenetic data with RNAseq expression data provides additional information pertaining to the mechanism of disease by correlating expression changes with underlying chromatin modifying processes and providing initial insights into the mechanisms of disease. These studies identify genes and/or regulatory regions that potentially have causative roles in the development or progression of disease. Further mechanistic studies focusing on the roles of each correlated gene/regulatory region will then provide additional understanding of the disease and targets for therapeutic interventions. Incorporation of genetic and lifestyle data will also improve analysis by integrating the full spectrum of risk into studies of disease mechanisms.