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

Xiaokang Zhang¹, Dingdong He², Yang Xiang¹

¹Center for Gene Diagnosis and Department of Clinical Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.

Translational Research : the Journal of Laboratory and Clinical Medicine

|April 23, 2022

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.

Insights

Dysferlin (DYSF) promoter hypermethylation increases its expression, promoting monocyte activation and contributing to atherosclerotic cardiovascular diseases (ASCVD). DYSF levels and methylation predict ASCVD risk.

Area of Science:

Cardiovascular Biology
Epigenetics
Molecular Medicine

Background:

Dysferlin (DYSF) impacts monocyte function, but its role in atherosclerotic cardiovascular diseases (ASCVD) and expression regulation remains unclear.
Investigating DYSF's role in ASCVD pathogenesis and its epigenetic regulation is crucial for understanding disease mechanisms.

Purpose of the Study:

To elucidate the role of Dysferlin (DYSF) in atherosclerotic cardiovascular diseases (ASCVD) pathogenesis.
To investigate the DNA methylation-driven regulation of DYSF expression in ASCVD.
To evaluate the functional impact of DYSF on monocyte behavior relevant to ASCVD.

Main Methods:

Utilized Gene Expression Omnibus (GEO) and EWAS data to identify DNA methylation-driven genes in ASCVD.
Performed weighted gene correlation network analysis (WGCNA) to find DYSF-related hub genes.
Validated DYSF promoter methylation, expression, and function in clinical samples, cell lines (THP1), and Apoe-/- mice.

Main Results:

Dysferlin (DYSF) promoter hypermethylation was confirmed to upregulate DYSF expression in ASCVD patients, THP1 cells, and Apoe-/- mice.
DYSF expression and promoter methylation in peripheral blood leucocytes (PBLs) showed significant predictive value for ASCVD.
Dysferlin (DYSF) enhanced monocyte phagocytosis, migration, and adhesion, with SELL identified as a downstream target.

Conclusions:

Dysferlin (DYSF) promoter hypermethylation upregulates its expression, driving monocyte activation and contributing to atherosclerotic cardiovascular diseases (ASCVD) pathogenesis.
DYSF is identified as a DNA methylation-driven gene with a significant role in ASCVD.
DYSF's functional enhancement of monocyte activities highlights its potential as a therapeutic target in ASCVD.

Read full analysis

Keywords:

1stExon ABR ABR activator of RhoGEF and GTPase ASCVD Cq DEG DM DMG DMP DNA methyltransferase 1 DNMT1 DYSF EWAS FBG FH GAPDH GSEA HD HDL-C HUVEC LDL-C MDRE ND PBL PLT PPI RPS27 SELL STAT3 TC TG TMX1 TOM TSS Tm UTR WBC WGCNA WT annealing temperature atherosclerotic cardiovascular diseases diabetes mellitus differentially expressed gene differentially methylated gene differentially methylated probe dysferlin epigenome-wide association study familial hypercholesterolemia fasting blood glucose gene set enrichment analysis glyceraldehyde-3-phosphate dehydrogenase high-density lipoprotein cholesterol high-fat diet human umbilical vein endothelial cell low-density lipoprotein cholesterol methylation dependent restriction enzyme methylation-specific qPCR normal diet ox-LDL oxidized low-density lipoprotein peripheral blood leukocyte platelet protein-protein interaction qMSP quantification cycle ribosomal protein S27 selectin L signal transducer and activator of transcription 3 the first exon thioredoxin related transmembrane protein 1 topological overlap matrix total cholesterol transcriptional start site triglyceride untranslated region weighted correlation network analysis white blood cell wild type

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