Down-Regulation of CXXC5 De-Represses MYCL1 to Promote Hepatic Stellate Cell Activation.

Xiaoyan Wu,Zhengyi Zhu,Longcheng Shang,Ming Kong,Wei Zhu,Xiaolei Shi,Wenhui Dong,Haozhen Ren,Jinglin Wang

doi:10.3389/fcell.2021.680344

Abstract

Liver fibrosis is mediated by myofibroblasts, a specialized cell type involved in wound healing and extracellular matrix production. Hepatic stellate cells (HSC) are the major source of myofibroblasts in the fibrotic livers. In the present study we investigated the involvement of CXXC-type zinc-finger protein 5 (CXXC5) in HSC activation and the underlying mechanism. Down-regulation of CXXC5 was observed in activated HSCs compared to quiescent HSCs both in vivo and in vitro. In accordance, over-expression of CXXC5 suppressed HSC activation. RNA-seq analysis revealed that CXXC5 influenced multiple signaling pathways to regulate HSC activation. The proto-oncogene MYCL1 was identified as a novel target for CXXC5. CXXC5 bound to the proximal MYCL1 promoter to repress MYCL1 transcription in quiescent HSCs. Loss of CXXC5 expression during HSC activation led to the removal of CpG methylation and acquisition of acetylated histone H3K9/H3K27 on the MYCL1 promoter resulting in MYCL1 trans-activation. Finally, MYCL1 knockdown attenuated HSC activation whereas MYCL1 over-expression partially relieved the blockade of HSC activation by CXXC5. In conclusion, our data unveil a novel transcriptional mechanism contributing to HSC activation and liver fibrosis.

Highlights

Liver fibrosis is a key intermediate step in such irreversible liver diseases as hepatocellular carcinoma and cirrhosis (Luedde and Schwabe, 2011)
We first evaluated the relationship between CXXC-type zinc-finger protein 5 (CXXC5) expression and Hepatic stellate cells (HSC) activation in different animal and cell models of liver fibrosis
In the first model liver fibrosis was induced in mice by bile duct ligation (BDL); liver fibrosis was evident as examined by picrosirius red staining (Figure 1A, left panel) and hydroxylproline quantification (Figure 1A, right panel)

Summary

Introduction

Liver fibrosis is a key intermediate step in such irreversible liver diseases as hepatocellular carcinoma and cirrhosis (Luedde and Schwabe, 2011). Mederacke et al (2013) have tracked the fate of emerging myofibroblasts in liver fibrosis using the lineage-tracing technique and discovered that this unique population of cells are invariably derived from hepatic stellate cells tucked between the sinusoidal endothelium and the parenchyma. Quiescent hepatic stellate cells (HSCs) are marked by the expression of desmin and lecithin retinol acyltransferase (lrat) and function mainly as a reservoir for lipids and vitamin A. Transcriptomic analyses reveal profound changes in gene expression patterns when quiescent HSCs become fully activated myofibroblasts in the fibrotic livers (Dobie et al, 2019; Marcher et al, 2019; Liu et al, 2020)

Methods

Results

Conclusion