Exportin 4 DNA promoter methylation in liver fibrosis

PLoS One. 2024 May 9;19(5):e0302786. doi: 10.1371/journal.pone.0302786. eCollection 2024.

Abstract

A role for exportin 4 (XPO4) in the pathogenesis of liver fibrosis was recently identified. We sought to determine changes in hepatic XPO4 promoter methylation levels during liver fibrosis. The quantitative real-time RT-PCR technique was used to quantify the mRNA level of XPO4. Additionally, pyrosequencing was utilized to assess the promoter methylation status of XPO4. The methylation rate of the XPO4 promoter was significantly increased with fibrosis in human and mouse models, while XPO4 mRNA expression negatively correlated with methylation of its promoter. DNA methyltransferases (DNMTs) levels (enzymes that drive DNA methylation) were upregulated in patients with liver fibrosis compared to healthy controls and in hepatic stellate cells upon transforming growth factor beta (TGFβ) stimulation. The DNA methylation inhibitor 5-Aza or specific siRNAs for these DNMTs led to restoration of XPO4 expression. The process of DNA methylation plays a crucial role in the repression of XPO4 transcription in the context of liver fibrosis development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Methylation*
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Humans
  • Karyopherins* / genetics
  • Karyopherins* / metabolism
  • Liver Cirrhosis* / genetics
  • Liver Cirrhosis* / metabolism
  • Liver Cirrhosis* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Karyopherins
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Xpo4 protein, human
  • Xpo4 protein, mouse

Grants and funding

Mohammed Eslam and Jacob George are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206) and Project and ideas grants (APP2001692, APP1107178 and APP1108422). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.