Abstract
Little is known regarding the epigenetic basis of atherosclerosis. Here we present the CD14+ blood monocyte transcriptome and epigenome signatures associated with human atherosclerosis. The transcriptome signature includes transcription coactivator, ARID5B, which is known to form a chromatin derepressor complex with a histone H3K9Me2-specific demethylase and promote adipogenesis and smooth muscle development. ARID5B CpG (cg25953130) methylation is inversely associated with both ARID5B expression and atherosclerosis, consistent with this CpG residing in an ARID5B enhancer region, based on chromatin capture and histone marks data. Mediation analysis supports assumptions that ARID5B expression mediates effects of cg25953130 methylation and several cardiovascular disease risk factors on atherosclerotic burden. In lipopolysaccharide-stimulated human THP1 monocytes, ARID5B knockdown reduced expression of genes involved in atherosclerosis-related inflammatory and lipid metabolism pathways, and inhibited cell migration and phagocytosis. These data suggest that ARID5B expression, possibly regulated by an epigenetically controlled enhancer, promotes atherosclerosis by dysregulating immunometabolism towards a chronic inflammatory phenotype.
Highlights
Little is known regarding the epigenetic basis of atherosclerosis
At Exam 5, carotid ultrasound and computed tomography (CT), were used to quantify carotid plaque burden and coronary artery calcification (CAC Agatston score), respectively. These two measures of atherosclerosis burden independently predict future cardiovascular disease (CVD) events in Multi-Ethnic Study of Atherosclerosis (MESA) and other cohorts[16,17,18,19]
In summary, using purified blood monocytes (CD14+) we discovered many epigenome and transcriptome features of atherosclerosis independent of well-known CVD risk factors, including several robust signals that were cross-validated by two state-of-art imaging measures of atherosclerosis, at different study sites, in two different arterial beds, and in both males and females
Summary
Little is known regarding the epigenetic basis of atherosclerosis. Here we present the CD14+ blood monocyte transcriptome and epigenome signatures associated with human atherosclerosis. In lipopolysaccharide-stimulated human THP1 monocytes, ARID5B knockdown reduced expression of genes involved in atherosclerosis-related inflammatory and lipid metabolism pathways, and inhibited cell migration and phagocytosis These data suggest that ARID5B expression, possibly regulated by an epigenetically controlled enhancer, promotes atherosclerosis by dysregulating immunometabolism towards a chronic inflammatory phenotype. Epigenome-wide studies of CVD traits are limited[6] and their interpretation is potentially complicated by use of data from mixed cell types, which may obscure cell-typespecific functional mechanisms. Monocytes and their derived macrophages are key factors in inflammation that contribute to the development of many chronic diseases, including atherosclerosis[7,8,9,10]. We show emerging evidence for a potential role of ARID5B in atherogenesis, and for an epigenetically controlled regulatory site of ARID5B expression
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