DYSF promotes monocyte activation in atherosclerotic cardiovascular disease as a DNA methylation-driven gene.

Abstract

Dysferlin (DYSF) has drawn much attention due to its involvement in dysferlinopathy and was reported to affect monocyte functions in recent studies. However, the role of DYSF in the pathogenesis of atherosclerotic cardiovascular diseases (ASCVD) and the regulation mechanism of DYSF expression have not been fully studied. In this study, Gene Expression Omnibus (GEO) database and epigenome-wide association study (EWAS) literatures were searched to find the DNA methylation-driven genes (including DYSF) of ASCVD. The hub genes related to DYSF were also identified through weighted correlation network analysis (WGCNA). Regulation of DYSF expression through its promoter methylation status was verified using peripheral blood leucocytes (PBLs) from ASCVD patients and normal controls, and experiments on THP1 cells and Apoe-/- mice. Similarly, the expressions of DYSF related hub genes, mainly contained SELL, STAT3 and TMX1, were also validated. DYSF functions were then evaluated by phagocytosis, transwell and adhesion assays in DYSF knock-down and overexpressed THP1 cells. The results showed that DYSF promoter hypermethylation up-regulated its expression in clinical samples, THP1 cells and Apoe-/- mice, confirming DYSF as a DNA methylation-driven gene. The combination of DYSF expression and methylation status in PBLs had a considerable prediction value for ASCVD. Besides, DYSF could enhance the phagocytosis, migration and adhesion ability of THP1 cells. Among DYSF related hub genes, SELL was proven to be the downstream target of DYSF by wet experiments. In conclusion, DYSF promoter hypermethylation upregulated its expression and promoted monocytes activation, which further participated in the pathogenesis of ASCVD.

• Authors: Xiaokang Zhang, Dingdong He, Yang Xiang, Chen Wang, Bin Liang, Boyu Li, Daoxi Qi, Qianyun Deng, Hong Yu, Zhibing Lu, Fang Zheng
• Journal: Translational research : the journal of laboratory and clinical medicine (Transl Res) Vol. 247 Pg. 19-38 (09 2022) ISSN: 1878-1810 [Electronic] United States
• PMID: 35460889 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Apolipoproteins E
• DYSF protein, human
• Dysf protein, mouse
• Dysferlin

Topics

• Animals
• Apolipoproteins E (metabolism)
• Atherosclerosis (genetics, metabolism)
• Cardiovascular Diseases (metabolism)
• DNA Methylation
• Dysferlin (genetics, metabolism)
• Humans
• Mice
• Monocytes (metabolism)