An Updated Review of the Epigenetic Mechanism Underlying the Pathogenesis of Age-related Macular Degeneration

Li, Xiaohua; He, Shikun; Zhao, Mingwei

doi:10.14336/ad.2019.1126

Cited by 14 publications

(6 citation statements)

References 118 publications

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“…The aging epigenome and transcriptome of cells in the retina undergo changes that correlate with decreased visual function and increased cell death [3][4][5]. Importantly, disruption of epigenetic mechanisms is associated with the onset of age-related eye diseases, such as age-related macular degeneration [6,7], suggesting that transcriptional regulation contributes to the changes in homeostasis that are observed in the aging eye. However, we still have only a basic understanding of how the molecular mechanisms that drive the age-associated changes in the transcriptome increase the risk of ocular disease with advanced age.…”

Section: Introductionmentioning

confidence: 99%

The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

et al. 2022

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The aging eye experiences physiological changes that include decreased visual function and increased risk of retinal degeneration. Although there are transcriptomic signatures in the aging retina that correlate with these physiological changes, the gene regulatory mechanisms that contribute to cellular homeostasis during aging remain to be determined. Here, we integrated ATAC-seq and RNA-seq data to identify 57 transcription factors that showed differential activity in aging Drosophila photoreceptors. These 57 age-regulated transcription factors include two circadian regulators, Clock and Cycle, that showed sustained increased activity during aging. When we disrupted the Clock:Cycle complex by expressing a dominant negative version of Clock (ClkDN) in adult photoreceptors, we observed changes in expression of 15–20% of genes including key components of the phototransduction machinery and many eye-specific transcription factors. Using ATAC-seq, we showed that expression of ClkDN in photoreceptors leads to changes in activity of 37 transcription factors and causes a progressive decrease in global levels of chromatin accessibility in photoreceptors. Supporting a key role for Clock-dependent transcription in the eye, expression of ClkDN in photoreceptors also induced light-dependent retinal degeneration and increased oxidative stress, independent of light exposure. Together, our data suggests that the circadian regulators Clock and Cycle act as neuroprotective factors in the aging eye by directing gene regulatory networks that maintain expression of the phototransduction machinery and counteract oxidative stress.

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Section: Introductionmentioning

confidence: 99%

The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

et al. 2022

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“…For instance, rare and common variants located within ncRNA-coding genes may impact on their expression and activity whereas other variants are methylation quantitative trait loci (meQTLs) able to influence methylation patterns. 60,82,83 The analysis of epigenomic signatures characterizing disease-associated tissues can be performed in high-resolution studies that encompass Next Generation Sequencing (NGS)-based technologies (RNA-seq, ATAC-seq, ChIPseq) and global chromosome conformation capture techniques (Hi-C). These methodologies need to be applied on relevant affected and non-affected tissues, such as the retina and the blood, to understand not only local but also systemic effects of disease-related signatures.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epigenomic signatures in age-related macular degeneration: Focus on their role as disease modifiers and therapeutic targets

Caputo

Strafella

Termine

et al. 2021

European Journal of Ophthalmology

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Epigenetics is characterized by molecular modifications able to shape gene expression profiles in response to inner and external stimuli. Therefore, epigenetic elements are able to provide intriguing and useful information for the comprehension and management of different human conditions, including aging process, and diseases. On this subject, Age-related Macular Degeneration (AMD) represents one of the most frequent age-related disorders, dramatically affecting the quality of life of older adults worldwide. The etiopathogenesis is characterized by an interplay among multiple genetic and non-genetic factors, which have been extensively studied. Nevertheless, a deeper dissection of molecular machinery associated with risk, onset, progression and effectiveness of therapies is still missing. In this regard, epigenetic signals may be further explored to disentangle disease etiopathogenesis, the possible therapeutic avenues and the differential response to AMD treatment. This review will discuss the epigenomic signatures mostly investigated in AMD, which could be applied to improve the knowledge of disease mechanisms and to set-up novel or modified treatment options.

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“…In the aging eye, cells in the retina undergo changes in DNA methylation and gene expression that correlate with decreased visual function and increased cell death 3 – 7 . Moreover, epigenetic mechanisms are implicated in the development and pathology of ocular diseases such as age-related macular degeneration 8 , 9 . These data suggest that the disruption of the chromatin landscape in the aging eye contributes to changes in its transcriptome, potentially increasing the risk of ocular disease.…”

Section: Introductionmentioning

confidence: 99%

Establishing the contribution of active histone methylation marks to the aging transcriptional landscape of Drosophila photoreceptors

Jauregui-Lozano

McGovern

Bakhle

et al. 2023

Sci Rep

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Studies in multiple organisms have shown that aging is accompanied by several molecular phenotypes that include dysregulation of chromatin. Since chromatin regulates DNA-based processes such as transcription, alterations in chromatin modifications could impact the transcriptome and function of aging cells. In flies, as in mammals, the aging eye undergoes changes in gene expression that correlate with declining visual function and increased risk of retinal degeneration. However, the causes of these transcriptome changes are poorly understood. Here, we profiled chromatin marks associated with active transcription in the aging Drosophila eye to understand how chromatin modulates transcriptional outputs. We found that both H3K4me3 and H3K36me3 globally decrease across all actively expressed genes with age. However, we found no correlation with changes in differential gene expression. Downregulation of the H3K36me3 methyltransferase Set2 in young photoreceptors revealed significant changes in splicing events that overlapped significantly with those observed in aging photoreceptors. These overlapping splicing events impacted multiple genes involved in phototransduction and neuronal function. Since proper splicing is essential for visual behavior, and because aging Drosophila undergo a decrease in visual function, our data suggest that H3K36me3 could play a role in maintaining visual function in the aging eye through regulating alternative splicing.

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An Updated Review of the Epigenetic Mechanism Underlying the Pathogenesis of Age-related Macular Degeneration

Cited by 14 publications

References 118 publications

The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

Epigenomic signatures in age-related macular degeneration: Focus on their role as disease modifiers and therapeutic targets

Establishing the contribution of active histone methylation marks to the aging transcriptional landscape of Drosophila photoreceptors

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