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Fibrosis following injury is a common adaptive response in the liver, which can lead to irreparable and life-threatening cirrhosis and hepatocellular carcinoma without effectual intervention. The molecular mechanisms underlying fibrogenic response in the liver remains poorly understood. Here we report that mice with deficiency in myocardin-related transcription factor A (MRTF-A) showed resistance to thioacetamide (TAA)-induced liver fibrosis with significantly reduced expression of pro-fibrogenic genes when compared to wild type littermates. Over-expression of MRTF-A enhanced whereas depletion of MRTF-A alleviated pro-fibrogenic transcription induced by TGF-β, a major pro-fibrogenic factor in hepatic stellate cells (HSCs). Mechanistically, MRTF-A silencing in HSCs impacted the chromatin structure by reducing the deposition of methylated histone H3K4 on the promoters of pro-fibrogenic genes. Further analyses revealed that MRTF-A interacted with and recruited several key epigenetic factors involved in H3K4 methylation, including ASH2, WDR5, and SET1, to the promoters of pro-fibrogenic genes in response to TGF-β treatment. Over-expression of ASH2, WDR5, or SET1 enhanced the transactivation of pro-fibrogenic gene promoters by TGF-β in an MRTF-A-dependent manner. In conclusion, MRTF-A regulates liver fibrosis by epigenetically tuning the TGF-β signaling pathway in HSCs. [ABSTRACT FROM AUTHOR]

Trans-differentiation, or activation, of hepatic stellate cells (HSCs) is a hallmark event in liver fibrosis although the underlying mechanism is not fully appreciated. Serum response factor (SRF) is a pleiotropic sequence-specific transcription factor with a ubiquitous expression pattern. In the present study, we investigated the effect of HSC-specific ablation of SRF on liver fibrosis in vivo and the underlying mechanism. We report that SRF bound to the promoter regions of pro-fibrogenic genes, including collagen type I (Col1a1/Col1a2) and alpha smooth muscle actin (Acta2), with greater affinity in activated HSCs compared to quiescent HSCs. Ablation of SRF in HSCs in vitro downregulated the expression of fibrogenic genes by dampening the accumulation of active histone marks. SRF also interacted with MRTF-A, a well-documented co-factor involved in liver fibrosis, on the pro-fibrogenic gene promoters during HSC activation. In addition, SRF directly regulated MRTF-A transcription in activated HSCs. More importantly, HSC conditional SRF knockout (CKO) mice developed a less robust pro-fibrogenic response in the liver in response to CCl4 injection and BDL compared to wild-type littermates. In conclusion, our data demonstrate that SRF may play an essential role in HSC activation and liver fibrosis. Key messages: • SRF deficiency decelerates activation of hepatic stellate cells (HSCs) in vitro. • SRF epigenetically activates pro-fibrogenic transcription to promote HSC maturation. • SRF interacts with MRTF-A and contributes to MRTF-A transcription. • Conditional SRF deletion in HSCs attenuates BDL-induced liver fibrosis in mice. • Conditional SRF ablation in HSCs attenuates CCl4-induced liver fibrosis in mice. [ABSTRACT FROM AUTHOR]

Fibrosis is a common pathophysiological process following liver injury and can lead to, if left unattended to, irreversible end-stage liver disease such as cirrhosis. Hepatic stellate cells (HSCs) are a major contributor to liver fibrosis. Here we investigated the involvement of angiogenic factor with G patch and FHA domains 1 (Aggf1) in HSC activation and the underlying mechanisms. Aggf1 expression was down-regulated in the livers in three different mouse models of liver fibrosis following injury. Aggf1 expression was also suppressed in activated HSCs when compared to quiescent HSCs. Over-expression of Aggf1 alleviated liver fibrosis in mice and in cultured HSCs. RNA-sequencing (RNA-seq) analysis performed in HSCs revealed that Aggf1-dependent transcription regulates several key fibrogenic pathways. Mechanistically, Aggf1 regulated liver fibrogenesis by forming a complex with the inhibitor SMAD protein (SMAD7) thereby leading to diminished SMAD3 binding to the pro-fibrogenic gene promoters. On the contrary, SMAD7 knockdown abrogated the effect of Aggf1 and rescued HSC activation. Aggf1 expression was silenced during HSC activation/liver fibrogenesis as a result of DNA methylation. Treatment with a DNA methyltransferase inhibitor (5-Azacytidine) restored Aggf1 expression and repressed liver fibrosis in an Aggf1-dependent manner. In conclusion, our data illustrate a previously unknown role for Aggf1 and shed light on the development of novel therapeutic solutions against liver fibrosis. [ABSTRACT FROM AUTHOR]