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High-throughput single cell RNA-sequencing of developing lens for cataract gene discovery

ABSTRACT: The eye lens contains anteriorly localized epithelial cells (anterior epithelium of lens, AEL) and posteriorly localized fiber cells (FCs). Cells in the AEL are further distinguished based on their proliferative indexes, while FCs can be distinguished based on their differentiation stages. Thus far, lens transcriptomics has focused on whole lens tissue samples or entire populations of AEL or FCs, and has provided key insights into lens pathobiology. Now, with recent advances, single-cell RNA-sequencing (scRNA-seq) can inform on cell-specific transcript heterogeneity and lead to new insights into pathological changes in individual cells that may contribute toward cataract. To make this approach practicable for wide applicability, we developed a working protocol for lens scRNA-seq that can be applied to tissue samples subjected to short-term storage, and used it to characterize embryonic and newborn mouse lens.

ORGANISM(S): Mus musculus

PROVIDER: GSE207991 | GEO | 2025/12/01

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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High-throughput single cell RNA-sequencing of developing lens for cataract gene discovery

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