Differentially expressed microRNAs in the aqueous humor of patients with exfoliation glaucoma or primary open-angle glaucoma

Drewry, Michelle; Challa, Pratap; Kuchtey, John; Navarro, Iris; Helwa, Inas; Hu, Yanzhong; Mu, Hongmei; Stamer, W. Daniel; Kuchtey, Rachel W.; Liu, Yutao

doi:10.1093/hmg/ddy040

Cited by 92 publications

(85 citation statements)

References 88 publications

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“…RNA quantity was measured using the Tecan microplate reader M200 (Tecan Group Ltd., Mannedorf, Zurich, Switzerland), and RNA quality was evaluated using the Agilent Bioanalyzer 2100 with RNA Pico Chips. 100 ng of total RNA was used to measure the expression of 800 pre-selected human miRNAs using the nCounter Human v3 miRNA expression assay kit from NanoString Technologies (Seattle, WA, USA), as previously described (31). After specific sample preparation and overnight hybridization, digital readouts of the relative miRNA abundance were obtained, translating to miRNA expression.…”

Section: Methodsmentioning

confidence: 99%

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Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

Drewry

Cai

Helwa

et al. 2018

Preprint

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Purpose Regulation of intraocular pressure is dependent upon homeostatic responses of trabecular meshwork (TM) cells to mechanical stretch. Despite the important roles of miRNAs in regulating TM function and aqueous outflow, it remains unclear how miRNA and their target genes interact in response to physiological cyclic mechanical stretch. We aimed to identify differentially expressed miRNAs and their potential targets in human TM cells in response to cyclic mechanical stress.Methods Monolayers of TM cells from non-glaucomatous donors (n=3-6) were cultured in the presence or absence of 15% mechanical stretch, 1 cycle/s, for 6 or 24-hours using computer-controlled Flexcell Unit. We profiled the expression of 800 miRNAs using NanoString Human miRNA assays and identified differentially expressed miRNAs using the Bioconductor Limma package. We identified differentially expressed genes using Operon Human Oligo Arrays with GeneSpring software. Pathway analysis with WebGestalt identified stretch-related pathways. We used Integrative miRNA Target Finder from Ingenuity Pathway Analysis to identify potential miRNA-mRNA regulations. ResultsWe identified 540 unique genes and 74 miRNAs with differential expression in TM cells upon cyclic mechanical stretch. Pathway analysis indicated the significant enrichment of genes involved in Wnt-signaling, receptor protein serine/threonine kinase signaling, TGF-β pathway, and response to unfolded protein. We also identified several miRNA master regulators, including miR-19b-3p and miR-93-5p, which may act as switches to control several mechano-responsive genes. ConclusionsThis study suggests that cyclic mechanical stress of TM cells triggers alterations in the expression of both mRNAs and miRNAs implicated in glaucoma-associated pathways.

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Section: Methodsmentioning

confidence: 99%

“…The raw data RCC files produced by nCounter were processed with the NanoString nSolver 3.0 software using a previously described analysis pipeline (31). Each sample was run through several quality control checks before analysis.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

Drewry

Cai

Helwa

et al. 2018

Preprint

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“…By conducting a microarray analysis of the differential expression of miRNA in the aqueous humour of glaucoma patients, several glaucoma-related extracellular miR-NAs have been identified (Tanaka et al 2014). Further investigation, through analysing both POAG and XFG patients, showed that three miR-NAs between POAG and control, five miRNAs between XFG and controls and one miRNA (miR-302d-3p) between POAG and XFG exhibited significant differences in expression (Drewry et al 2018). These miRNAs are likely to be involved in some glaucoma pathways including focal adhesion, tight junctions and TGF-b signalling pathways (Drewry et al 2018).…”

Section: Epigenetic Factors: Mirnamentioning

confidence: 99%

“…Further investigation, through analysing both POAG and XFG patients, showed that three miRNAs between POAG and control, five miRNAs between XFG and controls and one miRNA (miR‐302d‐3p) between POAG and XFG exhibited significant differences in expression (Drewry et al. ). These miRNAs are likely to be involved in some glaucoma pathways including focal adhesion, tight junctions and TGF‐ β signalling pathways (Drewry et al.…”

Section: Epigenetic Factors: Mirnamentioning

confidence: 99%

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Recent advances in risk factors associated with ocular exfoliation syndrome

Sharaf

Damji

Unsworth

2019

Acta Ophthalmologica

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Exfoliation syndrome is generally considered a progressive age‐related systemic disorder of the extracellular matrix, which is clinically characterized through the observation of flaky white aggregates on ocular tissues. Exfoliation syndrome is directly linked to exfoliative glaucoma in elderly patients, where it is known as the most common identifiable cause of open‐angle glaucoma. Despite the identification of various risk factors associated with exfoliation syndrome, the exact pathogenesis of this syndrome has not been fully elucidated. There is a growing number of genome‐wide association studies in different populations around the world to identify genetic factors underlying exfoliation syndrome. Besides variants in LOXL1 and CACNA1A genes, new loci have been recently identified which are believed to be associated with exfoliation syndrome. Among different genetic factors, functional variants might help to better understand mechanisms underlying this systemic disorder. Besides genetic factors, epigenetic regulation of different gene expression patterns has been thought to play a role in its pathogenesis. Other factors have been also considered to be involved in the development of exfoliation syndrome at cellular organelles level where mitochondrial impairment and autophagy dysfunction have been suggested in relation to exfoliation syndrome. This review addresses the most recent findings on genetic factors as well as cellular and molecular mechanisms involved in both the development and progression of exfoliation syndrome.

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Novel mutation in EFEMP1 identified from two Chinese POAG families differentially activated endoplasmic reticulum stress markers and induced glaucoma in mouse

Xiao,

Chen,

et al. 2023

J of Cellular Biochemistry

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Primary open‐angle glaucoma (POAG) is the most common type of glaucoma. Using whole‐exome sequencing, we identified two independent families diagnosed as POAG from the China with a novel EFEMP1 variant (Exon3, c.175A>C p.Met59Leu); Three previously reported variants c.1160G>A p.R387Q, c.1189T>C p.Y397H, and c.1429C>T p.R477C in EFEPM1 from 55 sporadic POAG individuals were also identified. The variant c.175A>C p.Met59Leu co‐segregated with the disease phenotype within the families. Immunoprecipitation and western blot assays showed that all three EFEMP1 mutants (p.Met59Leu, pArg140Trp, pArg345Trp) increased intracellular protein aggregations, and pMet59Leu and pArg140Arg also enhanced their extracellular proteins secretion, compared to WT in HEK293T. The differential regulations to endoplasmic reticulum (ER) stress markers ATF4, GPR78/94, and CHOP, and differential phosphorylation activations to CREB at Ser133, AKT at Ser473, p44/42 at Thr202/Tyr204, and STAT3 at Tyr705, were also detected among the mutants and WT. Finally, we revealed a significant increment of intraocular pressure and obvious reduction of RGC cells at the sixth week following intravitreal injection of adenovirus 5 (Ad5) expressing in pMet59Leu compared to WT and GFP controls. Together, variant c.175A>C p.Met59Leu in EFEMP1 is pathogenic and different mutants in EFEMP1 triggered distinct signaling pathways, explaining the reason of mutation‐dependent disease phenotypes of EFEMP1.

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Differentially expressed microRNAs in the aqueous humor of patients with exfoliation glaucoma or primary open-angle glaucoma

Cited by 92 publications

References 88 publications

Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

Recent advances in risk factors associated with ocular exfoliation syndrome

Novel mutation in EFEMP1 identified from two Chinese POAG families differentially activated endoplasmic reticulum stress markers and induced glaucoma in mouse

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