Traversing the epigenetic landscape: DNA methylation from retina to brain in development and disease

Abstract

DNA methylation plays a crucial role in development, aging, degeneration of various tissues and dedifferentiated cells. This review explores the multifaceted impact of DNA methylation on the retina and brain during development and pathological processes. First, we investigate the role of DNA methylation in retinal development, and then focus on retinal diseases, detailing the changes in DNA methylation patterns in diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma. Since the retina is considered an extension of the brain, its unique structure allows it to exhibit similar immune response mechanisms to the brain. We further extend our exploration from the retina to the brain, examining the role of DNA methylation in brain development and its associated diseases, such as Alzheimer's disease (AD) and Huntington's disease (HD) to better understand the mechanistic links between retinal and brain diseases, and explore the possibility of communication between the visual system and the central nervous system (CNS) from an epigenetic perspective. Additionally, we discuss neurodevelopmental brain diseases, including schizophrenia (SZ), autism spectrum disorder (ASD), and intellectual disability (ID), focus on how DNA methylation affects neuronal development, synaptic plasticity, and cognitive function, providing insights into the molecular mechanisms underlying neurodevelopmental disorders.

Keywords: Alzheimer’s disease and Huntington’s disease; DNA methylation and DNA demethylation; age-related macular degeneration; autism spectrum disorder; diabetic retinopathy; glaucoma; intellectual disability; schizophrenia.

Figure 1

Regions associated with neurodegenerative diseases in the brain and retina. (A) Schematic diagram of the human retina, showing the organization of different cell layers. ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. (B) The basic structure of the visual pathway. Axons of retinal ganglion cells (RGCs) form the ON, which extends to the LGN and SC in the brain. ON, optic nerve; OC, Optic chiasm; LGN, lateral geniculate nucleus; SC, superior colliculus. (C) The illustration presents the brain structures, including the hippocampus and dorsal striatum, which are associated with Alzheimer’s disease (AD) and Huntington’s disease (HD), respectively. It also highlights the brain functions involving the retina, such as sensory processing, memory formation, and learning. (D) The illustration depicts the differentiation of retinal progenitor cells from the embryonic stage to adulthood into various photoreceptors in mice, highlighting the distinct nuclear organization of rod and cone cells. Epigenetic markers such as 5mC, H3K27ac, and H3K4me3 are shown to illustrate chromatin modifications during this process.

Figure 2

Epigenetic modification factors and processes. (A) Schematic representations of the domain structures of human DNMT and TET isoforms, along with mUHRF1, are shown. PCNA, PCNA-interacting domain; NLS, nuclear localization signal; RFTS, replication foci-targeting sequence; CXXC, two cysteines separated by two other residues; BAH1/2, tandem bromo-adjacent homology; PWWP, Pro-Trp-Trp-Pro; ADD: ATRX-DNMT3-DNMT3L. DSBH, double-stranded β-helix; TTD, tandem tudor domain; PHD, plant homeodomain; SRA, Set and Ring Associated domain; RING, Really Interesting New Gene finger domain. (B) TET-mediated DNA demethylation pathway diagram. (1) Initial methylation: DNMTs catalyze the formation of 5mC. (2) Oxidation by TET proteins: 5mC is gradually oxidized by TET enzymes to generate 5hmC, 5fC, and 5caC. 5mC: 5-methylcytosine; 5hmC: 5-hydroxymethylcytosine; 5fC: 5-formylcytosine; 5caC: 5-carboxylcytosine. (3) Repair and demethylation: 5hmC, 5fC, and 5caC are excised by thymine DNA glycosylase (TDG) through the base excision repair (BER) pathway, ultimately restoring cytosine and completing the demethylation cycle. Additionally, passive demethylation occurs through dilution during cell division. (C) Mechanisms responsible for maintaining DNA methylation by the DNMT1/UHRF1 complex. This section illustrates the role of the DNMT1/UHRF1 complex in recognizing hemimethylated DNA and recruiting necessary enzymes for maintaining methylation patterns during DNA replication. Epigenetic modifications such as H3K9 methylation and H3 ubiquitination are also shown as key regulatory elements in this process.

Figure 3

Comparison of changes in the eye among normal, non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR), and the signaling pathways of DNA methylation alterations associated with DR development. (A) Schematic diagram illustrating changes in the eye under normal, NPDR, and PDR conditions. Normal eye: The retinal vascular network is well-organized and intact, with no signs of abnormal proliferation or damage. The vascular barrier is fully functional. NPDR eye: Shows microvascular abnormalities, including tortuosity, dilation, and microaneurysms. The vascular barrier is compromised, potentially accompanied by mild edema or exudates. PDR eye: Displays significant retinal damage with severe compromise of the vascular barrier, resulting in extensive exudation and hemorrhage. Notable features include extensive neovascularization. BM: basement membrane. (B) Mechanisms of DNA methylation changes and cellular function alterations in a hyperglycemic environment. High Glucose induces oxidative stress and epigenetically modulates the expression of TET2 and DNMT1. Elevated TET2 levels decrease methylation of the matrix metalloproteinase-9 (MMP-9) and Ras-related C3 botulinum toxin substrate 1 (Rac1) promoters, enhancing their expression and disrupting mitochondrial homeostasis and signaling pathways. Concurrently, increased DNMT1 activity leads to hypermethylation of the Timp1 and proliferator-activated receptor alpha (PPARα) promoters, suppressing their expression. These changes result in increased MMP-9 activity, compromised antioxidant defenses, and elevated apoptosis. Additionally, high Glucose levels correlate with increased methylation in the mitochondrial D-loop and base mismatches, impairing mitochondrial biogenesis and function, thereby affecting cellular energy metabolism and survival.

Figure 4

Schematic diagrams of normal retina, different types of age-related macular degeneration (AMD), and risk factors for AMD. (A) Schematic diagrams illustrating the normal retina and various stages of AMD. Normal Retina: Displays a healthy retinal structure with distinct layers, including the photoreceptor cells, without any pathological signs. Early AMD: Characterized by the appearance of small yellow deposits called drusen on BM, indicating early retinal changes. Intermediate AMD: Shows increased drusen size and number, along with pigmentary changes in the RPE, indicating progression of retinal degeneration. Advanced dry AMD: Marked by extensive drusen accumulation, significant RPE and photoreceptor cell loss, and widespread retinal atrophy. Neovascular AMD: Characterized by abnormal blood vessel growth (neovascularization), leading to hemorrhage, fluid leakage, and severe retinal damage. Geographic atrophy: Further characterized by the progressive enlargement of atrophic areas in the retina, leading to substantial vision loss. IS: inner segments; OS: outer segments; BM: Bruch’s membrane. (B) The impact of DNA methylation on AMD mechanisms. Hypomethylation of IL17RC leads to its upregulation, while hypermethylation of GSTM1 and GSTM5, along with their downregulation, promotes a series of biological processes in RPE cells, including lipid deposition, oxidative stress, inflammatory response, and mitochondrial dysfunction.

Figure 5

Glaucoma classification and cell type changes related to DNA Methylation alterations. (A) Diagram of two types of glaucoma. Primary open-angle glaucoma (POAG): The most common type of glaucoma, characterized by increased resistance to aqueous humor drainage through the trabecular meshwork, leading to elevated intraocular pressure and progressive optic nerve damage. Primary angle-closure glaucoma (PACG): A less common type, characterized by a sudden increase in intraocular pressure due to the obstruction of drainage pathways by the iris, potentially causing acute vision loss. MRZ-99030: A compound that mitigates vision loss in glaucoma by targeting and neutralizing amyloid-beta (Aβ) oligomers. (B) Role of TET enzymes in TM fibrosis. TET enzymes maintain hypomethylation of the growth differentiation factor 7 (GDF7) promoter, activating the bone morphogenetic protein receptor type 2 (BMPR2) /Smad signaling pathway and inducing the expression of pro-fibrotic genes such as α-smooth muscle actin (α-SMA), fibronectin, leading to TM fibrosis and obstruction of aqueous humor outflow. (C) Axon regeneration in injured optic nerve. The ectopic expression of Oct4, Sox2, and Klf4, along with TET1 and TET2, restores youthful DNA methylation in RGCs and promotes regeneration of damaged axons. (D) TGFβ1-induced epithelial-mesenchymal transition (EMT) and DNA methylation changes. TGFβ1 induces EMT in human conjunctival epithelial cells, leading to increased methylation of the miR-200 loci, which can be reversed by 5-Azacytidine (5-AzaC) treatment. (E) DNA methylation alterations in glaucomatous lamina cribrosa cells result in reduced methylation of the TGFβ1 promoter. This leads to increased expression of TGFβ1, αSMA, and collagen 1α1 (COL1A1), ultimately promoting fibrosis.

Figure 6

The Impact of DNA Methylation on Schizophrenia. (A) GABAergic pathway. GABA A, B, C R: Gamma-Aminobutyric Acid Type A, B, C Receptor. (B) Dopaminergic pathway. L-DOPA: L-3,4-dihydroxyphenylalanine; Met: Methionine; SAM: S-Adenosyl Methionine; SAH: S-Adenosyl Homocysteine. (C) Endocannabinoid system. CB1: Cannabinoid Receptor Type 1. (D) HPA Axis: Hypothalamic–Pituitary–Adrenal Axis; CRH: Corticotropin-Releasing Hormone; ACTH: Adrenocorticotropic Hormone. (E) Serotonergic pathway. 5-HTP: 5-Hydroxytryptophan; 5-HT: Serotonin; MAO: Monoamine Oxidase; VMAT2: Vesicular MonoAmine Transporter 2; SV: Synaptic Vesicle.

Figure 7

The role of DNA methylation changes in the pathogenesis of HD and the cellular impact of toxic huntingtin protein variants. (A) Production of toxic huntingtin protein variants. The huntingtin gene generates various toxic protein variants through multiple pathways, including RNA hairpins, abnormal repeat-associated non-ATG (RAN) translation protein products, amino-terminal huntingtin protein exon 1 protein fragment, and small fragments from full-length mutant huntingtin (mHTT). These fragments aggregate to form large inclusions in the cytoplasm and nucleus, contributing to cellular toxicity. (B) Cellular impact of toxic mHTT fragments. Nucleus: Toxic mHTT fragments disrupt nuclear processes, leading to transcriptional dysregulation and impaired DNA repair mechanisms. Factors such as DNA methylation changes, aging, and environmental influences exacerbate these effects, resulting in dysregulated transcription of important genes, including those involved in DNA repair. Mitochondria: mHTT fragments cause mitochondrial dysfunction, characterized by decreased ATP production, impaired mitochondrial protein import, autophagy damage, and increased oxidative stress, which contribute to metabolic dysfunction. Synapse: Toxic mHTT fragments affect synaptic function, leading to abnormal synaptic transmission, neuronal death, and decreased brain-derived neurotrophic factor (BDNF) levels. This results in altered synaptic plasticity, dysregulated neurotransmitter release, and neuronal dysfunction, ultimately progressing to cell death. Interventions with 5-AzaC, 5-Fluoro-2′-deoxycytidine (FdCyd), and decitabine have been shown to reverse transcriptional dysregulation and synaptic dysfunction, highlighting potential therapeutic strategies.

Figure 8

The critical roles of DNA methylation in AD. (A) Impact of AD pathology on hippocampal structure. AD pathology in the hippocampus is characterized by neuronal dysfunction and degeneration, activation of inflammatory responses, and abnormal deposition of Aβ plaques and tau protein neurofibrillary tangles. These factors collectively contribute to the progression of AD. (B) DNA methylation differences between AD and healthy brains. In healthy brains, DNMT1 maintains DNA methylation, while DNMT3A and DNMT3B facilitate de novo methylation. TET enzymes convert 5mC to 5hmC, 5fC, and 5caC, which are then demethylated back to cytosine. In AD brains, this balance is disrupted, leading to abnormal methylation patterns that contribute to disease progression. (C) Influence of DNA methylation changes on AD progression. In AD, DNA methylation balance is disrupted, resulting in hypermethylation and hypomethylation of specific genes, altering their expression. Hypoxic conditions exacerbate this imbalance by inhibiting DNMT3B expression, triggering increased deposition of Aβ and tau proteins, and worsening AD pathology. Mitochondrial dysfunction, including disrupted membrane permeability and impaired electron transport chain activity, leads to oxidative stress. This is accompanied by abnormal hypermethylation of mitochondrial genes such as CYTB and COX II, along with decreased mitochondrial DNA (mtDNA) copy numbers, resulting in neuronal death and accelerating AD progression. (1) Alkaloids (DNLA) reduces Aβ production by promoting the hypermethylation of APP and BACE1; (2) Berberine maintains mitochondrial homeostasis by promoting the hypermethylation of PINK1. Additionally, MRZ-99030 mitigates Aβ deposition by targeting and neutralizing Aβ oligomers.