HDAC4 stimulates MRTF-A expression and drives fibrogenesis in hepatic stellate cells by targeting miR-206

Abstract

Activation of hepatic stellate cells (HSCs) is a hallmark event during liver fibrogenesis. We have previously shown that the transcriptional modulator MRTF-A contributes to liver fibrosis by programming epigenetic activation of HSCs. In the present study we investigated the mechanism whereby MRTF-A expression is regulated in this process. We report here that MRTF-A protein levels, but not mRNA levels, were up-regulated in vivo in the livers of mice induced to develop hepatic fibrosis. Pro-fibrogenic stimuli (TGF-β and PDGF-BB) also activated MRTF-A expression post-transcriptionally in vitro in cultured HSCs. miR-206 bound to the 3′-UTR of MRTF-A presumably to inhibit translation. miR-206 levels were down-regulated in response to pro-fibrogenic stimuli in vivo and in vitro allowing MRTF-A proteins to accumulate. Mechanistically, histone deacetylase 4 (HDAC4) was induced by pro-fibrogenic stimuli and recruited to the miR-206 promoter to repress miR-206 transcription. HDAC4 stimulated MRTF-A expression and drove fibrogenesis in HSCs in a miR-206 dependent manner. Therefore, our data reveal an HDAC4-miR-206-MRTF-A axis that can play a potentially important role in HSC activation and liver fibrosis.