Abstract
Defective cholesterol biosynthesis in eye lens cells is often associated with cataracts; however, how genes involved in cholesterol biosynthesis are regulated in lens cells remains unclear. Here, we show that Quaking (Qki) is required for the transcriptional activation of genes involved in cholesterol biosynthesis in the eye lens. At the transcriptome level, lens-specific Qki-deficient mice present downregulation of genes associated with the cholesterol biosynthesis pathway, resulting in a significant reduction of total cholesterol level in the eye lens. Mice with Qki depletion in lens epithelium display progressive accumulation of protein aggregates, eventually leading to cataracts. Notably, these defects are attenuated by topical sterol administration. Mechanistically, we demonstrate that Qki enhances cholesterol biosynthesis by recruiting Srebp2 and Pol II in the promoter regions of cholesterol biosynthesis genes. Supporting its function as a transcription co-activator, we show that Qki directly interacts with single-stranded DNA. In conclusion, we propose that Qki-Srebp2–mediated cholesterol biosynthesis is essential for maintaining the cholesterol level that protects lens from cataract development.
Highlights
Defective cholesterol biosynthesis in eye lens cells is often associated with cataracts; how genes involved in cholesterol biosynthesis are regulated in lens cells remains unclear
Another isoform, Qki-6 was highly localized to the nucleus similar to Qki-5, but the expression of Qki-6 was only 30% decreased in green fluorescent protein (GFP)+ lens cells of QkiCKO mice at P19 (Supplementary Fig. 1e, f), potentially due to the relatively higher stability of Qki-6 compared to Qki-5, suggesting that depletion of Qki-5 is responsible for the phenotypic alteration in eye lens from the Qk-iCKO mice shown below
We further revealed that the reductions of Srebp[2] and polymerase II (Pol II) binding on the promoters of the genes highly bound by Srebp[2] were significantly correlated with the downregulations of gene expressions upon Qki depletion as cholesterol biosynthesis genes such as mevalonate diphosphate decarboxylase (Mvd), Hmgcs[1], methylsterol monooxygenase 1 (Msmo1), Sc5d, farnesyl diphosphate synthase (Fdps), Hmgcr, Mvk, and phosphomevalonate kinase (Pmvk) all fell into this gene cluster as shown in Fig. 6k, suggesting that Qki-5 is essential for transcriptional enhancement of these cholesterol biosynthesis genes
Summary
Defective cholesterol biosynthesis in eye lens cells is often associated with cataracts; how genes involved in cholesterol biosynthesis are regulated in lens cells remains unclear. We show that Quaking (Qki) is required for the transcriptional activation of genes involved in cholesterol biosynthesis in the eye lens. Whereas most tissues use both of these mechanisms to meet the needs for cellular cholesterol[2], some cholesterol-rich tissues, such as eye lens and brain, in which the supply of cholesterol from plasma lipoproteins is stringently limited, depend extensively on de novo cholesterol biosynthesis[5,6] How these tissues meet the high demand for cholesterol biosynthesis remains largely unknown. Studying cholesterol biosynthesis in the eye lens may identify transcriptional regulators of SREBP2 and provide insight into tissue-specific cholesterol homeostasis
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