Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99287 | GEO | 2018/03/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Systems-level analysis of age-related macular degeneration reveals global and subtype-specific functional pathways

Project description:Age-related macular degeneration (AMD) is a leading cause of human blindness in developed countries. While significant inroads have been made over the past decade, an integrated description of the molecular mechanisms underlying AMD has yet to emerge. Here we describe a systems-level transcriptome analysis of the retina and retinal pigmented epithelium (RPE)-choroid complex from 31 normal, 26 AMD, and 11 potential pre-AMD human eyes derived from the University of Iowa. Our analysis identifies cell-mediated immune responses as the central feature of dry AMD, wet AMD, and geographic atrophy (GA), and we confirm this finding using a second cohort of donor eyes obtained from the Lion's Eye Bank of Oregon. In addition, in the RPE-choroid, we identify the major up-regulated pathways in GA and wet AMD as apoptosis and angiogenesis, respectively. In the retina, a graded up-regulation of wound response, complement, and neurogenesis pathway genes strongly correlates with advanced stages of AMD, in parallel with a progressive down-regulation of key phototransduction processes. Finally, using expression signatures enriched in functional pathways, we assemble two detailed AMD interactomes that highlight modular gene expression programs that delineate and interconnect dry, wet, and GA AMD subtypes across both RPE-choroid and retina tissues. In total, these interactomes are comprised of over 150 genes of which 23 have been previously associated with AMD. These data provide new insights into the expression landscape of AMD pathophysiology, and reveal numerous new targets for AMD pharmaceuticals and diagnostics.

2012-02-14 | GSE29801 | GEO

An in vitro model of chronic wounding and its implication for age-related macular degeneration

Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. In this study we investigated changes in differentated human retinal pigmented epithelial (RPE) cells to acute compared to chronic wounding. There are many interesting phenotypic and transcriptomic changes that occur after chronic wounding compared to acute wounding conditions which may have implications for AMD.

2020-07-08 | GSE146884 | GEO

Extracellular vesicles confer disease phenotype in Y402H-retinal pigment epithelium cell model of age-related macular degeneration.

Project description:Age related macular degeneration (AMD) is a leading cause of legal blindness. Vision loss is caused by the retinal pigment epithelium (RPE) and photoreceptors loss and/or retinal and choroidal angiogenesis. Here we report enhanced polarised secretion of extracellular vesicles (EVs) in complement factor H (CFH) Y402H AMD patient specific RPE. As indicated by multi ‘omics analyses, AMD RPE EVs carry a repertoire of RNA, proteins and lipids that reflect disease changes in the RPE cells of origin and mediate pathological processes such as oxidative stress, cytoskeletal dysfunction and angiogenesis. We demonstrate that exposure of control RPE to AMD RPE EVs leads to the formation of numerous cytoplasmic stress vacuoles, cytoskeletal destabilization, and abnormalities in the morphology of the nucleus in the recipient cells. Treatment of laminated retinal organoids containing photoreceptor cells with apical AMD RPE EVs leads to disrupted neuroepithelium and appearance of enlarged cells immunopositive for cytoprotective alpha B crystallin. The presence of cells expressing alpha B crystallin and progenitor cells markers Pax6 or Vsx2 are consistent with the activation of regenerative pathways upon injury. These findings suggest that AMD RPE EVs act as signalling messengers in the outer retina and may be involved in disease progression.

2022-12-28 | GSE190263 | GEO

Dissecting genetic components associated with eye disease using integrative genomic analysis [RNA-seq]

Project description:GWAS studies have revealed thousands of variants strongly associated with AMD, yet connecting these variants to their cognate genes has not been explored. In this study we fine-mapped AMD risk loci and examined long-range cis chromatin interactions at essential genes of RPE function and disease-associated variants in iPSC-induced retinal pigmented epithelium (RPE) and primary RPE.

2022-04-30 | GSE201680 | GEO

Dissecting genetic components associated with eye disease using integrative genomic analysis [ChIP-seq]

2022-04-30 | GSE201679 | GEO

Dissecting genetic components associated with eye disease using integrative genomic analysis [Capture HiC]

2022-04-30 | GSE201678 | GEO

Dissecting genetic components associated with eye disease using integrative genomic analysis [ATAC-seq]

2022-04-30 | GSE201677 | GEO

The LHX2-OTX2 regulatory module controls RPE differentiation and underlies a causal regulatory risk-SNP in age-related macular degeneration

Project description:Tissue-specific transcription factors control the transcriptome through an association with noncoding regulatory regions (cistromes). Identifying the combination of transcription factors that dictate specific cell fate, their specific cistromes and examining their involvement in complex human traits remain a major challenge. Here we focus on the retinal pigmented epithelium (RPE), an essential lineage for retinal development and function and the primary tissue affected in age-related macular degeneration (AMD), a leading cause of blindness. By combining mechanistic findings in stem-cell-derived human RPE, in- vivo functional studies in mice and global transcriptomic and proteomic analyses, we revealed that the key developmental transcription factors LHX2 and OTX2 function together in transcriptional module containing LDB1 and SWI/SNF (BAF) to regulate the RPE transcriptome. Importantly, the intersection between the identified LHX2-OTX2 cistrome with published expression quantitative trait loci, ATAC-seq data from human RPE, and AMD GWAS data, followed by functional validation using a reporter assay, revealed a causal genetic variant that affects AMD risk by altering TRPM1 expression in the RPE through modulation of LHX2 transcriptional activity on its promoter. Taken together, the reported cistrome of LHX2 and OTX2, the identified downstream genes and interacting co-factors reveal the RPE transcription module and uncover a causal regulatory risk SNP in the multifactorial common blinding disease AMD.

2023-03-11 | PXD038485 | Pride

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

Project description: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.

2020-09-29 | GSE153817 | GEO

Epithelial phenotype restoring drugs suppress macular 1 degeneration phenotypes in an iPSC model

Project description:Age-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE) and atrophy of the RPE monolayer in advanced disease stages - leading to photoreceptor cell death and vision loss. Currently, there are no drugs to stop drusen formation or RPE atrophy in AMD. We developed an iPSC-RPE AMD model that recapitulates drusen and RPE atrophy. Drusen deposition is dependent on AMD-risk-allele CFH(H/H) and anaphylatoxin triggered alternate complement signaling via the activation of NF-B and downregulation of autophagy pathways. High-throughput screen identified two drugs, L-745,870, a dopamine receptor antagonist, and aminocaproic acid, a protease inhibitor that reduce drusen deposits and restore RPE epithelial phenotype in anaphylatoxin challenged iPSC-RPE with or without the CFH(H/H) genotype. This comprehensive iPSC-RPE model replicates key AMD phenotypes, provides molecular insight into the role of CFH(H/H) risk-allele in AMD, and discovers two candidate drugs to treat AMD.

2021-10-12 | GSE185310 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data