Histone deacetylase 4 represses matrix metalloproteinases in myofibroblastic hepatic stellate cells

UnrestrictedIt is well established that matrix metalloproteinases (MMPs) play important roles in tissue injury, cell differentiation, and cancer metastasis. In liver injury, hepatic stellate cells (HSCs) express high level of MMPs and undergo trans-differentiation to become myofibroblast like cells. However, largely unknown is that how MMP genes are repressed or silenced in tissue fibrosis to favor ECM accumulation. In this study, it was investigated how MMP genes were progressively repressed in fibrotic liver and myofibroblastic HSCs. First, it was shown that upon interleukin-1 (IL-1) stimulation, the major signaling pathways that are essential for MMP expression were as active in myofibroblastic HSCs as in quiescent HSCs, indicating the repression was attained at chromatin levels. Indeed, it was found that in myofibroblastic HSCs both MMP-9 and MMP-13 genes were less accessible for transcriptional factors, which was associated with impaired histone acetylation and RNA polymerase II recruitment to the promoters. Further, it was observed that during HSC trans-differentiation, the class II histone deacetylase HDAC4 accumulated, in accordance with global reduction of histone acetylation. To demonstrate a causal relationship of HDAC4 elevation in MMP gene repression, HDAC4 was ectopically expressed in quiescent HSCs, which resulted in sufficient repression of MMP promoter activities as well as endogenous MMP-9 protein expression. Thus, a mechanism was uncovered about how MMP genes are epigenetically silenced in tissue fibrogenesis partially through HDAC4 accumulation