Stat3 is a mediator for TGFβ1 regulating bromodomain protein 4 and cross-talks with Smad3 signaling and Egr-1 in hepatic stellate cell

Abstract

Abstract Background Bromodomain protein 4 (BrD4), an epigenetic reader, functions as a global genomic regulator to direct hepatic stellate cell (HSC) activation and liver fibrogenesis. Our recent researches demonstrated the effect of TGFβ1, a pivotal pro-fibrotic cytokine, on BrD4 expression through Smad3/Egr1 axis in HSCs. Stat3 is widely acknowledged as a regulator of gene transcription and involved in fibrosis of many tissues. The present study was focused on the roles of Stat3, a non-canonical signaling of TGFβ1, in TGFβ1 regulating BrD4 in HSCs and examined the relationship among Stat3 signaling, Smad3 signaling, and Egr1. Methods Heterogeneous TGFβ1 knockout mice and thioacetamide-induced liver injury were employed. Adeno-associated virus encoding shRNA were for knockdown of gene expression in vivo. Mouse HSCs were used in vitro. Results Stat3 mediated TGFβ1-induced BrD4 expression in vitro and in vivo. BrD4 knockdown lessened Stat3- induced HSC activation and liver fibrosis. TGFβ1-induced Smad3 pathway activated Stat3 signaling which at least promoted Egr1 binding to BrD4 promoter for BrD4 expression. Egr1 knockdown significantly reduced the effect of Stat3 signaling on BrD4 expression and Egr1 had a positive feedback on Stat3 activation in HSCs. Moreover, an increase in BrD4 expression paralleled to Stat3 activation in activated HSCs in human cirrhotic livers. Thus, a network consisting of Stat3 signaling, Smad3 signaling, Egr1, and BrD4 emerged, which contributed to the effects of TGFβ1 on HSC activation and liver fibrosis. Conclusions Stat3 was another mediator for TGFβ1 regulating BrD4 and cross-talked with Smad3 and Egr-1. This report broadened the understanding of the roles of TGFβ1 in liver fibrogenesis.