Activation of Galectin-3 (LGALS3) Transcription by Injurious Stimuli in the Liver Is Commonly Mediated by BRG1

Galectin-3 (encoded by LGALS3) is a glycoprotein that regulates a diverse range of pathophysiological processes contributing to the pathogenesis of human diseases. Previous studies have found that Galectin-3 levels are up-regulated in the liver by a host of different injurious stimuli. The underlying epigenetic mechanism, however, is nuclear. Here we report that conditional knockout of BRG1, a chromatin remodeling protein, in hepatocytes attenuated induction of Galectin-3 expression in several different animal models of liver injury. Similarly, BRG1 depletion or pharmaceutical inhibition in cultured hepatocytes suppressed the induction of Galectin-3 expression by treatment with LPS plus free fatty acid (palmitate). Further analysis revealed that BRG1 interacted with AP-1 to bind to the proximal Galectin-3 promoter and activate transcription. Mechanistically, DNA demethylation surrounding the Galectin-3 promoter appeared to be a rate-limiting step in BRG1-mediated activation of Galectin-3 transcription. BRG1 recruited the DNA 5-methylcytosine dioxygenase TET1 to the Galectin-3 to promote active DNA demethylation thereby activating Galectin-3 transcription. Finally, TET1 silencing abrogated induction of Galectin-3 expression by LPS plus palmitate in cultured hepatocytes. In conclusion, our data unveil a novel epigenetic pathway that contributes to injury-associated activation of Galectin-3 transcription in hepatocytes.