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Chromatin topology dynamics of dexamethasone-treated trabecular meshwork identifies 78 causal genes for intraocular pressure and primary open angle glaucoma [ATAC]

ABSTRACT: The physiology of trabecular meshwork (TM) controls aqueous humor outflow resistance and thereby intraocular pressure (IOP), a major risk factor for primary open-angle glaucoma (POAG). To decipher how GWAS-identified non-coding variants contribute to IOP and POAG, we generated a high-resolution map of genome topology and regulatory modules from primary human TM cell lines. Integrated analyses with dexamethasone-treated TM cells, a model of augmented IOP, demonstrate extensive changes in chromatin compartments, accessibility, looping, and histone marks that are highly concordant with transcriptional changes. By combining GWAS-associated variants with dexamethasone-induced chromatin looping, we discovered 26 IOP- and 52 POAG- candidate causal genes, belonging to key TM pathways, including integrin, transcriptional regulation of VENTX, and TNF signaling. Our studies provide a mechanistic framework for elucidating genetic complexity of IOP and pathogenesis of POAG and suggest new targets for therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301516 | GEO | 2026/04/10

REPOSITORIES: GEO

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Project description:Elevated intraocular pressure (IOP) is influenced by environmental and genetic factors. It is associated with 23 multiple disease processes with primary open angle glaucoma (POAG) being the most prevalent. Due to its 24 complex, multifactorial nature, genetic predisposition is not completely understood thus, there is an urgent 25 need for additional investigations into the genetic regulation of IOP. Heterogenous stock (HS) outbred rats are 26 a multigenerational outbred population derived from eight inbred strains that have been fully sequenced. This 27 population is ideal for genome-wide association studies (GWAS) due to the accumulated recombinations 28 among well-defined haplotypes, the relatively high allele frequencies, access to a large collection of tissue 29 samples, and the large allelic effect size compared to human studies. The purpose of this study was to identify 30 genetic loci underlying elevated IOP using HS rats. Both male and female HS rats (N=1,812) were used in the 31 study. Genotyping-by-sequencing was used to obtain ~3.5M single nucleotide polymorphisms from each 32 individual. We performed a GWAS for the IOP phenotype using a linear mixed model and used permutation to 33 determine a genome-wide significance threshold. We also estimated SNP heritabilities. Our GWAS results 34 identified three genome-wide significant loci for elevated IOP on chromosomes 1, 5, and 16. These loci 35 contained 7 genes in total including Tyr, Grm5, Ctsc, Rab38, MGC94199, Plekhf2, and Csmd1. We also 36 mapped expression quantitative trait loci (eQTLs) in HS rat eye tissue and discovered a cis-eQTL for Ctsc 37 among our significant loci. Tyr is the only gene that has been previously associated with human IOP. This 38 study highlights the efficacy of HS rats for investigating the genetics of elevated IOP and identifying potential 39 candidate genes for future functional testing. In summary, GWAS using HS rats is a powerful method for 40 identifying genome regions that harbor variants responsible for the variation in quantitative traits, such as IOP. 41 Additional studies are ongoing to further narrow the list of candidate genes in these intervals.

Project description:Purpose: Primary open-angle glaucoma (POAG) is the most common glaucoma with elevated intraocular pressure (IOP). Dysfunction of trabecular meshwork (TM) cells affects the outflow facility of aqueous humor, resulting in high IOP. Phagocytosis is an important function for TM cells, this study aims to identify phagocytosis related genes/proteins and the effect of lovastatin in glaucomatous TM cells. Methods: The phagocytic ability of immortal normal human TM cells (iHTM) and glaucomatous TM cells (GTM3) was detected by fluorescent beads and flow cytometry. RNA sequencing and proteomic analysis were used to identify different genes and proteins that potentially involved in regulating the phagocytic function of TM cells. The expression of low density lipoprotein receptor (LDLR) in iHTM and GTM3 was validated by immunofluorescence staining and Western blot. Lovastatin was used to test the effect of LDLR on the phagocytosis of TM cells. The expression of LDLR and the phagocytic ability was measured by western blot and fluorescent beads respectively. Results: The Phagocytosis of GTM3 was significantly weaker than that of iHTM. The integrated analysis upon the transcriptome and proteome identified 3 differentially expressed genes/proteins closely related to phagocytosis of cells, including DAB2: NM_001244871.1, DNAJC6: NM_001256864.1 and LDLR: NM_000527.4. Their expression in GTM3 was obviously lower than that in iHTM. In addition, we have further illustrated the decreased expression of LDLR in GTM3 by immunofluorescence staining and Western blot. However, Lovastatin was found to increase its expression and the phagocytosis ability of GTM3. Conclusions: Three phagocytosis-related genes/proteins were obviously decreased in GTM3 compared to iHTM, they might be responsible for the decreased phagocytic function of TM cells in glaucoma. The up-regulation of LDLR by Lovastatin can enhanced the phagocytosis of GTM3, suggesting Lovastatin might be a new potential medicine to promote the phagocytosis of TM cells in glaucoma.

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Chromatin topology dynamics of dexamethasone-treated trabecular meshwork identifies 78 causal genes for intraocular pressure and primary open angle glaucoma [ATAC]

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