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Epigenetic hallmarks of age-related macular degeneration are recapitulated in a photosensitive mouse model

ABSTRACT: Age-related macular degeneration (AMD) is a chronic, multifactorial disorder and a leading cause of blindness in the elderly. Characterized by progressive photoreceptor degeneration in the central retina, disease progression involves epigenetic changes in chromatin accessibility resulting from environmental exposures and chronic stress. Here, we report that a photosensitive mouse model of acute stress-induced photoreceptor degeneration recapitulates the epigenetic hallmarks of human AMD. Global epigenomic profiling by assay for transposase-accessible chromatin using sequencing (ATAC-Seq) revealed an association between decreased chromatin accessibility and stress-induced photoreceptor cell death in our mouse model. The epigenomic changes induced by light damage include reduced euchromatin and increased heterochromatin abundance, resulting in transcriptional and translational dysregulation that ultimately drives photoreceptor apoptosis and an inflammatory reactive gliosis in the retina. Through our findings, we identified key histone-modifying enzymes that contribute to the observed changes in global chromatin accessibility. Moreover, pharmacological inhibition of histone deacetylase 11 (HDAC11) and suppressor of variegation 3-9 homolog 2 (SUV39H2) ameliorated light damage in our mouse model, supporting a causal link between decreased chromatin accessibility and photoreceptor degeneration, thereby representing a potential new therapeutic strategy to combat AMD.

ORGANISM(S): Mus musculus

PROVIDER: GSE153817 | GEO | 2020/09/29

REPOSITORIES: GEO

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A widespread decrease of chromatin accessibility in age-related macular degeneration

Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. The extent to which epigenetic changes regulate the progression of AMD is unclear. Here we profiled chromatin accessibility in the retina and retinal pigmented epithelium (RPE) from AMD patients and controls. Global decreases in chromatin accessibility occur in the RPE in early AMD and in the retina with advanced disease. Footprints of photoreceptor and RPE-specific transcription factors are enriched in differentially accessible regions (DARs) and reduced AMD. Genes associated with DARs show altered expression in AMD. Cigarette smoke, an established risk factor for AMD, applied to human iPSC-derived RPE cells recapitulates epigenomic changes seen in AMD. In addition to providing a comprehensive profile of chromatin accessibility in human RPE and retina, this study shows that global decreases in chromatin accessibility may play a critical role in AMD progression.

2018-03-05 | GSE99287 | GEO

The deubiquitinase Otud7b suppresses cone photoreceptor degeneration in mouse models of retinal degenerative diseases

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2011-06-07 | E-GEOD-29752 | biostudies-arrayexpress

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Project description:Neural degenerative diseases often display a progressive loss of cells at as a stretched exponential ratedistribution. The mechanisms underlying the survival of a subset of clonal cells in a population beyond what is expected by chance alone remains unknown. To gain mechanistic insights underlying prolonged cellular survival, we used Spata7 mutant mice as a model and performed single-cell transcriptomic profiling of retinal tissue along the time course of photoreceptor degeneration. Intriguingly, rod cells that survive beyond the initial rapid cell apoptosis phase progressively acquire a distinct transcriptome profile. In these rod cells, expression of photoreceptor-specific phototransduction pathway genes is downregulated while expression of other retinal cell type-specific marker genes is upregulated. These transcriptomic changes are achieved by direct modulation of the epigenomeetic modifications and changes of the chromatin state at these gene loci, as indicated by immunofluorescence staining and single-cell ATAC-seq. Consistent with this model, when the induction of the repressive epigenetic state is blocked by in vivo histone deacetylase HDAC inhibition, all photoreceptors in the mutant retina undergo rapid degeneration, strongly curtailing the stretched exponential distribution. Altogether, oOur study reveals an intrinsic mechanism by which the neuralon cells progressively adapt to the genetic stress to achieve prolonged survival through epigenomic regulation and chromatin state modulation.

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Methylation data from human retina samples profiled with Infinium HumanMethylationEPIC BeadChip

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Protective gene expression changes elicited by an inherited defect in photoreceptor structure.

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2011-12-31 | E-GEOD-33134 | biostudies-arrayexpress

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Project description:Age-related macular degeneration (AMD) is a complex multifactorial disease with at least 34 loci contributing to genetic susceptibility. To gain functional understanding of AMD genetics, we generated transcriptional profiles of retina from 453 individuals including both controls and cases at distinct stages of AMD. We integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 noncoding genes, with genotypes at over 9 million common single nucleotide polymorphisms (SNPs) for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets. Cis-eQTL analysis revealed 10,474 genes under genetic regulation, including 4,541 eQTLs detected only in the retina. We then integrated the AMD-genome-wide association studies (GWAS) data with eQTLs and ascertained target genes at six loci. Furthermore, using transcriptome wide association analysis (TWAS), we identified 23 additional AMD-associated genes, including RLBP1, HIC1 and PARP12. Our studies expand the genetic landscape of AMD leading to direct targets for biological evaluation and establish the Genotype-Retina Expression (GREx) database as a resource for post-GWAS interpretation of retina-associated traits including glaucoma and diabetic retinopathy.

2019-02-11 | GSE115828 | GEO

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