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Gene expression profile in the small Maf-deficient livers.

ABSTRACT: To elucidate the functional roles of sMafs in the adult liver, we conditionally targeted the sMaf genes using a transgenic complementation rescue approach. MafF-/-::MafG-/-::MafK-/- (F0G0K0) mice are embryonic lethal but can be rescued by complementation of transgenic MafG expression under the regulation of the MafG regulatory domain (MGRD). Therefore, we rescued F0G0K0 mice using a MGRD transgenic mouse line with a MafG gene flanked with loxP (fMafG) sequences so that the MafG gene could be deleted by Cre-mediated recombination. The Albumin(Alb)-Cre transgenic mice were used to delete fMafG gene specifically in the liver. The genotype used are MafF-/-::MafG-/-::MafK-/-::MGRD-fMafG::Alb-Cre (liver-specific sMaf CKO) and MafF-/-::MafG+/-::MafK-/-::MGRD-fMafG::Alb-Cre (control).

ORGANISM(S): Mus musculus

PROVIDER: GSE84001 | GEO | 2017/05/01

SECONDARY ACCESSION(S): PRJNA327793

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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Gene expression profile in the small Maf-deficient livers.

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