RFX1 downregulation contributes to TLR4 overexpression in CD14+ monocytes via epigenetic mechanisms in coronary artery disease

Abstract

BackgroundToll-like receptor 4 (TLR4) expression is increased in activated monocytes, which play a critical role in the pathogenesis of coronary artery disease (CAD). However, the mechanism remains unclear. Regulatory factor X1 (RFX1) is a critical transcription factor regulating epigenetic modifications. In this study, we investigated whether RFX1 and epigenetic modifications mediated by RFX1 contributed to the overexpression of TLR4 in activated monocytes.ResultsCompared with those of the controls, the mRNA and protein expression of RFX1 were downregulated and the mRNA expression of TLR4 was upregulated in CD14+ monocytes obtained from CAD patients and CD14+ monocytes obtained from healthy controls treated with low-density lipoprotein (LDL). The mRNA expression of RFX1 was negatively correlated with the mRNA expression of TLR4 in CD14+ monocytes. RFX1 knockdown led to the overexpression of TLR4 and the activation of CD14+ monocytes. In contrast, the overexpression of RFX1 inhibited TLR4 expression and the activation of CD14+ monocytes stimulated with LDL. Moreover, TLR4 was identified as a target gene of RFX1. The results indicated that RFX1 downregulation contributed to the decreased DNA methylation and histone H3 lysine 9 trimethylation and the increased H3 and H4 acetylation in the TLR4 promoter via the lack of recruitments of DNA methyltransferase 1 (DNMT1), histone deacetylase 1 (HDAC1), and histone-lysine N-methyltransferase SUV39H1 (SUV39H1), which were observed in CD14+ monocytes of CAD patients.ConclusionsOur results show that RFX1 expression deficiency leads to the overexpression of TLR4 and the activation of CD14+ monocytes in CAD patients by regulating DNA methylation and histone modifications, which highlights the vital role of RFX1 in the pathogenesis of CAD.Electronic supplementary materialThe online version of this article (10.1186/s13148-019-0646-9) contains supplementary material, which is available to authorized users.

Regulatory Factor X1 Downregulation Contributes to Monocyte Chemoattractant Protein-1 Overexpression in CD14+ Monocytes via Epigenetic Mechanisms in Coronary Heart Disease

“…More importantly, monocytes may be involved in the amplification of their own recruitment to inflammatory lesions by inducing MCP1 (Cushing and Fogelman, 1992). A previous study also showed a significant increase in MCP1 expression in CAD patients and LDL-treated monocytes (Du et al, 2019). However, the specific regulatory mechanisms of MCP1 overexpression in CD14+ monocytes are not fully understood.…”

“…RFX1 downregulation causes CD11a, CD70 and IL17A overexpression by reducing DNA methylation and increasing H3 acetylation levels in the promoter region of CD11a, CD70 and IL17A in the CD4+ T cells of systemic lupus erythematosus (SLE) patients, which contributes to autoimmune responses (Zhao et al, 2010a; Zhao et al, 2018). Our previous research also showed that RFX1 expression was downregulated in the CD14+ monocytes of CAD patients (Du et al, 2019).…”

“…Previous studies showed that RFX1 bound to target gene promoter region and regulated its epigenetic modification (Du et al, 2019; Zhao et al, 2010b). We further compared the enrichments of RFX1 and its related modification enzymes in MCP1 promoter region between CAD and non-CAD patients.…”

“…Recent studies have shown that abnormal epigenetic modification plays an important role in the pathogenesis of AS (Du et al, 2019). In apoE -/- mouse aortic plaques and peritoneal macrophages, hypermethylation of the cystathionine-gamma lyase ( CSE ) promoter region resulted in a reduction in CSE gene expression, thereby promoting AS development (Du et al, 2016).…”

Thioredoxin‐interacting protein promotes activation and inflammation of monocytes with DNA demethylation in coronary artery disease

“…Despite advances in prevention and treatment, coronary artery disease (CAD) remains a threat to human health worldwide due to atherosclerosis (AS) and its thrombotic complications. As we know, CAD is caused by combination of genetic and environmental factors .…”