Epigenetic Alterations in Age-Related Macular Degeneration: Mechanisms and Implications

Abstract

Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss among the elderly, and is influenced by a combination of genetic and environmental risk factors. While genetic associations in AMD are well-established, the molecular mechanisms underlying disease onset and progression remain poorly understood. A growing body of evidence suggests that epigenetic modifications may serve as a potential missing link regulating gene-environment interactions. This review incorporates recent findings on DNA methylation, including both hypermethylation and hypomethylation patterns affecting genes such as silent mating type information regulation 2 homolog 1 (SIRT1), glutathione S-transferase isoform (GSTM), and SKI proto-oncogene (SKI), which may influence key pathophysiological drivers of AMD. We also examine histone modification patterns, chromatin accessibility, the status of long non-coding RNAs (lncRNAs) in AMD pathogenesis and in regulating pathways pertinent to the pathophysiology of the disease. While the field of ocular epigenetics remains in its infancy, accumulating evidence to date points to a burgeoning role for epigenetic regulation in AMD, pre-clinical studies have yielded promising findings for the prospect of epigenetics as a future therapeutic avenue.

Keywords: DNA methylation; age-related macular degeneration; chromatin accessibility; epigenetics; histone acetylation; histone methylation; histone modifications; histone variants; long noncoding RNA.

Figure 4

Proposed interactions between epigenetic-genetic factors influencing AMD progression pathways. Epigenetic changes in methyl groups attached to cytosines in CpG dinucleotides (Me) act as epigenetic switches in genes associated with AMD onset and progression. Processes involved in AMD progression, inflammation, drusen formation, oxidative stress, and angiogenesis are driven by contrasting methylation patterns in a number of genes. Hypermethylation of promoter regions, where increased methyl groups are added to DNA, results in changes of gene expression in SIRT1 [132], LCAT [139], PRSS50 [136], and GTF2H4 [137] (left), which then drive AMD processes. In contrast, hypomethylated promoter regions, with decreased methylated bases, in GSTM1, GSTM5 [129,130], SKI [129,137], ANGPTL2 [138,145], IL17RC [131,144], and LINE-1 [132,139,140,141] (right) are associated with these AMD processes. This image was created using Procreate.

Figure 5

Influence of HDAC and HATs in AMD pathogenesis. Histone acetylation (HATs), such as P300, function by supporting an open chromatin state, activating transcription, which may result in increasing M2-type macrophage proliferation associated with increased susceptibility to nAMD [4,174]. Whereas, histone deacetylases (HDACs) support a closed chromatin state (condensation), inhibiting transcription [156]. Studies have demonstrated downregulation of HDAC1 [157,159] and HDAC3 [157,158] and downregulation of HDAC11 [160,177,178]. This causes dysregulation of key cellular processes, increasing susceptibility to inflammation, immunological dysregulation, oxidative stress, and angiogenesis, resulting in either nAMD or GA [19,157,158,159,160]. This Figure was created using Procreate and modified using Biorender [https://BioRender.com].

Figure 1

Stages of AMD progression. Key cellular and structural changes observed from early to late stages of disease. (A) Early AMD marked by the formation of small- to medium-sized drusen between the RPE and BrM. (B) Intermediate AMD is characterized by larger, confluent drusen formation as well as initial signs of RPE dysfunction. (C) Geographic atrophy (GA) is represented by RPE cell degeneration followed by secondary photoreceptor loss and choriocapillaris thinning. (D) Neovascular AMD (nAMD) is represented by abnormal blood vessel formation in the choroid through BrM into the RPE and retina, which causes leakage, hemorrhage, and scarring. This Figure was created using Procreate 5.3.15 and modified using Biorender [https://BioRender.com].

Figure 2

Genetic risk factors associated with AMD pathogenesis. Key genes associated with AMD pathogenesis classified into four subtypes: (1) the complement pathway genes, which may contribute to immune dysregulation, inflammation, and degeneration of the retina. (2) Angiogenesis and mitochondrial dysfunction genes, involved in CNV development, mitochondrial dysregulation, RPE degeneration, and photoreceptor loss. (3) Genes involved in lipid metabolism, influencing cholesterol and lipoprotein production, influencing drusen formation. (4) Genes associated with enhancing oxidative stress, influencing the regulation of mitochondria, immune cells, and stress responses, promoting retinal degeneration. This image was created using Biorender [https://BioRender.com] and Procreate.

Figure 3

Epigenetic mechanisms that have been investigated in the context of AMD. (1) Histone acetylation. (2) RNA-based mechanisms, including long noncoding RNA (lncRNA) and micro-RNA (miRNA). (3) Histone methylation. (4) DNA methylation. Mechanisms that promote open chromatin are signified by green histones, whereas mechanisms that promote closed chromatin are signified by pink histones. This image was created using Procreate.

Figure 6

Potential epigenetic therapeutic candidates in relation to AMD, and suggestions for future directions. Previously established targets for epigenetic mechanisms and suggested further directions, including: Constructing genome-wide epigenomic maps to identify enhancers, silencers, and super-enhancers; Histone variants (e.g., H3.3) and chaperones regulating cell survival; CRISPR-dCas9 tools to modulate DNA methylation and histone acetylation in disease; Next-generation sequencing (ChIP-seq, ATAC-seq, and RNA-seq) to identify transcription factors and chromatin states. This image has been created using Biorender [https://BioRender.com].