Epigenome-metabolism nexus in the retina: implications for aging and disease

Abstract

Intimate links between epigenome modifications and metabolites allude to a crucial role of cellular metabolism in transcriptional regulation. Retina, being a highly metabolic tissue, adapts by integrating inputs from genetic, epigenetic, and extracellular signals. Precise global epigenomic signatures guide development and homeostasis of the intricate retinal structure and function. Epigenomic and metabolic realignment are hallmarks of aging and highlight a link of the epigenome-metabolism nexus with aging-associated multifactorial traits affecting the retina, including age-related macular degeneration and glaucoma. Here, we focus on emerging principles of epigenomic and metabolic control of retinal gene regulation, with emphasis on their contribution to human disease. In addition, we discuss potential mitigation strategies involving lifestyle changes that target the epigenome-metabolome relationship for maintaining retinal function.

Keywords: DNA methylation; age-related macular degeneration; diet; environmental factors; gene regulation; histone modifications; metabolic pathways; multifactorial traits; vision impairment.

Figure 1:. A schematic of the interconnection between epigenome and metabolome.

Layers of epigenetic controls from DNA methylation on CpG dinucleotides, histone modifications including acetylation (Ac), lactylation (La), crotonylation (Cr), succinylation (Su) to higher level of chromatin architecture are shown on the left. Epigenomic studies assess genome-wide epigenetic features and determine regulatory status of key genes and processes. On the right, core metabolic pathways are depicted, highlighting production of metabolites that serve as co-substrates for epigenetic modifiers. This diagram visualizes the bi-directional feedback relationship between cellular metabolism and epigenomic gene regulation. Created with BioRender.com.

Figure 2:. Cell types and metabolic landscape of the retina.

(A) The retina has a multilayered structure of neural cells and pigmented epithelium (RPE). The RPE layer contacts the outer segments of the photoreceptors - rod and cone cells - present within the outer nuclear layer (ONL) of the neural retina. Photoreceptor axons synapse with interneurons - bipolar and horizontal cells – in the outer plexiform layer (OPL). Bipolar and amacrine cells connect with retinal ganglion cells to form the inner plexiform layer (IPL). Bipolar, horizontal and amacrine cells together comprise the inner nuclear layer (INL). Ultimately, retinal ganglion cells (RGCs) project via the the optic nerve to the visual cortex (Figure reproduced from [11]). (B) Metabolic and molecular exchange among retinal cells. Glycolysis is a key energy production pathway in photoreceptors and leads to significant lactate production. This lactate is taken up by RPE and Müller cells for use in TCA cycle and OXPHOS. Photoreceptor glycolysis also feeds into the pentose phosphate pathway (PPP) for biosynthesis of NADPH, nucleic acids and other anabolic molecules. The photoreceptors also utilize pyruvate for energy production via OXPHOS. RPE periodically phagocytoses photoreceptor outer segments, repurposing biomolecules such as fatty acids for β-oxidation. Moreover, RPE houses the visual cycle enzymes which convert all-trans-retinol from photoreceptors to 11-cis-retinal, the active chromophore in photoreceptor opsins. For cone photoreceptors, visual cycle is partially undertaken by Müller glia in a non-canonical pathway. Furthermore, Müller cells and phtoreceptors exchange glutamine for glutamate, respectively.

Figure 3:. Epigenome and metabolism-centered adaptation to extrinsic and intrinsic variables determines retinal homeostasis.

Schematic representation of key factors influencing retinal health via epigenomic and metabolic alterations. Changes in diet (supply of glucose, fatty acids, and nutrients), genotype (genetic variations), aging (including genomic instability), light exposure (e.g., to UV radiations), and hypoxia (that can produce reactive oxygen species, ROS) and stress perturb DNA methylation and histone modifications (epigenome) and/or metabolic pathways (impacting metabolite levels), thereby disrupting retinal gene regulatory network. Adaptation of the retina in healthy and/or disease states represents an equilibrium in the epigenome-metabolism relationship. Created with BioRender.com.

Figure 4:. Genetic regulation of retinal epigenome, metabolism, and gene expression.

Distinct quantitative trait locus (QTLs) modulate effects of genetic variants on epigenetic and metabolic features. Variants associated with methylation at CpG sites are known as methylation quantitative trait locus (mQTLs), those associated with histone post-translational modifications including H3K4me3, H3K27me3, H3K4me1, and H3K27ac, are known as histone quantitative trait locus (hQTLs) and those linked with metabolite abundance are measured by metabolic quantitative trait locus (meQTLs), respectively. Correlation of methylation status at DNA CpG sites and target gene expression can be tested by expression quantitative trait methylation (eQTM). Finally, epigenetic clock estimates biological age based on DNA methylation levels of curated CpG sites.