Abstract
Galectin-3 (encoded by LGALS3) is a glycan-binding protein 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 unclear. Here we report that conditional knockout of Brahma related gene (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.
Highlights
Transcriptional regulation in mammalian cells is acutely influenced by the epigenetic machinery, which includes DNA and histone modifying enzymes, chromatin remodeling proteins, and non-coding regulatory RNAs (Ledford, 2015)
Hepatocyte conditional BRG1 knockout (CKO) mice and wild type (WT) mice were subjected to different treatments of liver injury
Hepatic galectin-3 expression was significantly up-regulated in CCl4-injected mice at the mRNA (Figure 1A) and protein (Figure 1B) levels; galectin-3 induction was less robust in CKO mice than in WT mice
Summary
Transcriptional regulation in mammalian cells is acutely influenced by the epigenetic machinery, which includes DNA and histone modifying enzymes, chromatin remodeling proteins, and non-coding regulatory RNAs (Ledford, 2015). A host of chemical groups are superimposed on DNA and histone tails ( the prefix “epi-”) creating a layer of regulatory information (Shafabakhsh et al, 2019). Chromatins can be categorized into three groups based on characteristic DNA/histone modifications associated with the promoter region (Lennartsson and Ekwall, 2009). On the contrary, silenced chromatin regions are demarcated by high levels of DNA methylation (CpG) and histone H3K9/H3K27 methylation. The third group of chromatins possess both the “active” and the “repressive” DNA/histone markers and can be said to be labeled by “bivalent” modifications; removal of the “repressive” modifications potentiates transcription whereas erasure of the “active” modifications permanently turns off transcription (Harikumar and Meshorer, 2015)
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