Complete Transcriptome Profiling of Normal and Age-Related Macular Degeneration Eye Tissues Reveals Dysregulation of Anti-Sense Transcription

Kim, Young Ho; Grant, Gregory R.; Bowman, Anita S.; Haider, Naqi; Gudiseva, Harini V.; Chavali, Venkata R M

doi:10.1038/s41598-018-21104-7

Cited by 49 publications

(56 citation statements)

References 47 publications

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“…Analysis of the Gene Expression Omnibus datasets (https://www. ncbi.nlm.nih.gov/geo) confirmed absence of CFHR4 transcription in the neurosensory retina, RPE and choroid using Affymetrix U133plus2 human genome arrays 41 , Affymetrix Human Exon 1.0 ST arrays 42,43 or RNA sequencing 44,45 ( Supplementary Fig. 2b-f).…”

Section: Resultsmentioning

confidence: 78%

Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration

et al. 2020

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Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10 −6 ), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch's membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10 −56 ), independently of the AMD-protective CFHR1-3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.

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Section: Resultsmentioning

confidence: 78%

Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration

et al. 2020

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“…A role for miRNA-4470 mediated SUCNR1 mRNA reduction in AMD development is supported by expression of miRNA-4470 and SUCNR1 in human retina tissue. SUCNR1 is known to be expressed in human RPE-choroid tissue [30] ( Figure 1A) but miRNA-4470 has so far only been reported to be expressed in human immune [26] and microglia cells [31].…”

Section: Discussionmentioning

confidence: 99%

Single nucleotide polymorphism rs13079080 is associated with differential regulation of the succinate receptor 1 (SUCNR1) gene by miRNA-4470

et al. 2019

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Oxidative stress is a feature of many common diseases. It leads to excessive formation and subsequent release of the mitochondrial metabolite succinate, which acts as a signalling molecule through binding the succinate receptor (SUCNR1). Recently, a potential role for SUCNR1 was proposed in age-related macular degeneration (AMD), a common cause of vision loss in the elderly associated with increased oxidative stress. Here, we evaluated the potential effect of genetic variants in SUCNR1 on its expression through differential micro-RNA (miRNA) binding to target mRNA, and investigated the relevance of altered SUCNR1 expression in AMD pathogenesis. We analysed common SUCNR1 SNPs for potential miRNA binding sites and identified rs13079080, located in the 3ʹ-UTR and binding site for miRNA-4470. Both miRNA-4470 and SUCNR1 were found to be expressed in human retina. Moreover, using a luciferase reporter assay, a 60% decrease in activity was observed when miRNA-4470 was co-expressed with the C allele compared to the T allele of rs13079080. Finally, genotyping rs13079080 in an AMD case-control cohort revealed a protective effect of the TT genotype on AMD compared to the CC genotype (p = 0.007, odds ratio = 0.66). However, the association was not confirmed in the case-control study of the International AMD Genomics Consortium. Our study demonstrates that the T allele of rs13079080 in SUCNR1 disrupts a binding site for miRNA-4470, potentially increasing SUCNR1 expression and consequently increasing the capacity of sensing and dealing with oxidative stress. Therefore, it would be worthwhile assessing the relevance of rs13079080 in other oxidative stress-associated diseases in future studies.

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“…We cross-referenced our mouse splicing analysis with human RNA-Seq datasets generated by the GTEx consortium 29 . We also supplemented our analysis with datasets from peripheral retina 45 , since GTEx did not sequence retinal tissue. (A) Similar to our mouse splicing analysis, we find many exons that are brain-enriched and that some of these exons are also present in skeletal muscle and heart.…”

Section: Figure 2 Splicing Analysis Of the Gtex Database Reveals Retmentioning

confidence: 99%

“…HepG2 shRNA-Seq datasets generated by the ENCODE consortium (only a subset of the full data representing well known splicing factors, full database of all shRNA-Seq datasets is available at http://ascot.cs.jhu.edu/data), 3. Various GTEx tissues 29 and peripheral retina 45 as reference data (retina, brain, and skeletal muscle are highlighted in red). No HepG2 shRNA knockdown datasets are capable of activating rod-specific exons but overexpression of MSI1 followed by FACS isolation of the top 1% expressing cells can successfully activate rod-specific exons.…”

Section: Figurementioning

confidence: 99%

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ASCOT identifies key regulators of neuronal subtype-specific splicing

Ling

Wilks

Charles

et al. 2018

Preprint

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1Public archives of next-generation sequencing data are growing exponentially, but the difficulty of 2 marshaling this data has led to its underutilization by scientists. Here we present ASCOT, a resource that 3 allows researchers to summarize, visualize, and query alternative splicing patterns in public RNA-Seq 4 data. ASCOT enables rapid identification of splice-variants across tens of thousands of bulk and single-5 cell RNA-Seq datasets in human and mouse. To demonstrate the utility of ASCOT, we first focused on the 6 nervous system and identified many alternative exons used only by a single neuronal subtype. We then 7 leveraged datasets from the ENCODE and GTEx consortiums to study the unique splicing patterns of rod 8 photoreceptors and found that PTBP1 knockdown combined with overexpression of MSI1 and PCBP2 9 activates rod-specific exons in HepG2 liver cancer cells. Furthermore, we observed that MSI1 targets 10 intronic UAG motifs proximal to the 5' splice site and interacts synergistically with PTBP1 11 downregulation. Finally, we show that knockdown of MSI1 in the retina abolishes rod-specific splicing. 12This work demonstrates how large-scale analysis of public RNA-Seq datasets can yield key insights into 13 cell type-specific control of RNA splicing and underscores the importance of considering both annotated 14 and unannotated splicing events. ASCOT splicing and gene expression data tables, software, and 15 interactive browser are available at http://ascot.cs.jhu.edu. 16 17

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Complete Transcriptome Profiling of Normal and Age-Related Macular Degeneration Eye Tissues Reveals Dysregulation of Anti-Sense Transcription

Cited by 49 publications

References 47 publications

Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration

Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration

Single nucleotide polymorphism rs13079080 is associated with differential regulation of the succinate receptor 1 (SUCNR1) gene by miRNA-4470

ASCOT identifies key regulators of neuronal subtype-specific splicing

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