The Histone Demethylase KDM4D Promotes Hepatic Fibrogenesis by Modulating Toll-Like Receptor 4 Signaling Pathway

Abstract

Accumulating evidence has revealed the pivotal role of epigenetic regulation in the pathogenesis of liver disease. However, the epigenetic mechanism that accounts for hepatic stellate cells (HSCs) activation in liver fibrosis remains largely unknown. In this study, primary HSCs were used to screen the differentially expressed histone H3 lysine methyltransferases and demethylases during HSC activation. KDM4D was identified as a remarkable up-regulated histone H3 demethylase during HSC activation. The overexpression profile of KDM4D was further confirmed in three fibrosis animal models and human fibrotic liver tissues. In vitro genetic silencing of Kdm4d impaired the collagen gel contraction and migration capacity of primary HSCs. In established CCl4-induced mice model, Kdm4d knockdown inhibited fibrosis progression, and promoted fibrosis reversal, with enhanced thinning and splitting of fibrotic septa, as well as a dramatic decrease in collagen area. Whole gene transcriptome analysis showed the regulatory role of KDM4D in Toll-Like Receptor (TLR) signaling pathway. Mechanistically, KDM4D catalyzed histone 3 on lysine 9 (H3K9) di-, and tri-demethylation, which promoted TLR4 expression, and subsequently prompted liver fibrogenesis by activating NF-{kappa}B signaling pathways. KDM4D facilitates TLR4 transcription through demethylation of H3K9, thus activating TLR4/NF-{kappa}B signaling pathways in HSCs, contributing to HSC activation and collagen crosslinking, further, hepatic fibrosis progression.