Abstract
The Osmotic Response Element-Binding Protein (OREBP), also known as TonEBP or NFAT5, is a key tonicity-regulated transcription factor that regulates the expression of a battery of genes crucial for the adaptation of mammalian cells to extracellular hypertonic stress. In this study, we investigated the role of nucleosomes in hypertonicity-induced and OREBP-dependent gene transcription by using chromatin immunoprecipitation and real-time quantitative PCR analysis. Here, we demonstrated that histones within 2 kb upstream of the aldose reductase (AR) promoter are rapidly acetylated and phosphorylated upon hypertonic stress, suggesting a link between histone modifications and tonicity-regulated AR gene transcription. Furthermore, we determined that histone modification is associated with the loss of nucleosome integrity specifically at ORE site, which couples the recruitment of OREBP to the site. However, OREBP is not required for the loss of nucleosome integrity under hypertonic stress, since nucleosome loss was also observed in mouse embryonic fibroblasts derived from OREBP-deficient mice, although the level of nucleosome loss was less than in the cells derived from the wild-type mice. Our present data suggest that hypertonicity modifies the chromatin environment of the AR promoter to facilitate OREBP-dependent AR gene transcriptions.
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