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Transcriptome changes driving multiple regulatory pathways involved in TGF-β-induced Anterior Subcapsular Cataract

ABSTRACT: Transforming Growth Factor-beta (TGF-β) promotes lens epithelial-mesenchymal tran-sition (EMT) and fibrosis, contributing to anterior subcapsular cataract (ASC) formation. Transgenic mice overexpressing TGF-β1 in lens have been studied for over three decades, and yet the impact of active TGF-β1-overexpression on the lens epithelial transcriptome is undefined. We have addressed this knowledge gap by examining the gene expression landscape of these unique lens epithelia. High-throughput RNA-sequencing was per-formed on isolated lens epithelia from three-week-old TGF-β1-overexpression trans-genic mice from two independent lines, OVE853 and OVE918, and wild-type mice. Downstream analyses included comparisons with lens datasets (e.g., cataract-surgery model) and investigations using various resources/tools (e.g., Gene Ontology, CompBio, iSyTE). Compared to wild-type murine lens epithelia, 384 differentially expressed genes (DEGs) were commonly identified in lens of both transgenic lines. Candidates involved in EMT, inflammatory response, extracellular matrix organization, and mecha-no-sensation were elevated, while those involved in lipid metabolism, Wnt-suppression, Bmp- and Notch-activation were reduced. Comparative analyses with temporal tran-scriptomes on a mouse cataract-surgery model identified overlapping pathological pathways, and some elevated genes, for example endoplasmic reticulum stress genes, were in agreement with human ASC data. A major discovery was the identification of several novel TGF-β1-targets. All our data is made user-friendly accessible through iSyTE.

ORGANISM(S): Mus musculus

PROVIDER: GSE336537 | GEO | 2026/06/25

REPOSITORIES: GEO

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Project description:Although majority of the genes linked to pediatric cataract exhibit lens fiber cell-enriched expression, our understanding of gene regulation in these cells is limited to function of just eight transcription factors and largely in the context of crystallins. Here, we identify small Maf transcription factors MafG and MafK as regulators of several non-crystallin human cataract genes in fiber cells and establish their significance to cataract. We applied a bioinformatics tool for cataract gene discovery iSyTE to identify MafG and its co-regulators in the lens, and generated various null-allelic combinations of MafG:MafK mouse mutants for phenotypic and molecular analysis. By age 4-months, MafG-/-:MafK+/- mutants exhibit lens defects that progressively develop into cataract. High-resolution phenotypic characterization of MafG-/-:MafK+/- lens reveals severe defects in fiber cells, while microarrays-based expression profiling identifies 97 differentially regulated genes (DRGs). Integrative analysis of MafG-/-:MafK+/- lens-DRGs with 1) binding-motifs and genomic targets of small Mafs and their regulatory partners, 2) iSyTE lens-expression data, and 3) interactions between DRGs in the String database, unravels a detailed small Maf regulatory network in the lens, several nodes of which are linked to human cataract. This analysis prioritizes 36 highly promising candidates from the original 97 DRGs. Significantly, 8/36 (22%) DRGs are associated with cataracts in human (GSTO1, MGST1, SC4MOL, UCHL1) or mouse (Aldh3a1, Crygf, Hspb1, Pcbd1), suggesting a multifactorial etiology that includes elevation of oxidative stress. These data identify MafG and MafK as new cataract-associated candidates and define their function in regulating largely non-crystallin genes linked to mouse and human cataract. Microarray comparision of lenses from mixed background (129Sv/J, C57BL/6J, and ICR) control (MafG+/-:MafK+/-; no-cataract) and compound (MafG-/-:MafK+/-; cataract) mouse mutants

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Transcriptome changes driving multiple regulatory pathways involved in TGF-β-induced Anterior Subcapsular Cataract

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