Blood monocyte transcriptome and epigenome analyses reveal loci associated with human atherosclerosis

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.

Monocytes present age‐related changes in phospholipid concentration and decreased energy metabolism

“…In particular, CX3CR1, which binds fractalkine thereby promoting monocyte migration and cell adhesion, has been shown to direct monocytes to atherosclerotic lesions in blood vessels (Tacke et al, 2007). Our list of upregulated genes also includes the transcription factor AT‐rich interaction domain 5B (ARID5B), which has been shown to activate adipogenic gene expression and promote the expression on atherogenic markers in monocytes (Liu et al, 2017; Whitson, Tsark, Huang, & Itakura, 2003; Yamakawa, Whitson, Li, & Itakura, 2008) (Table ). Another highly upregulated gene was pyruvate dehydrogenase kinase 4 ( PDK4 ), which inhibits the pyruvate dehydrogenase complex, thereby shifting glucose metabolism from oxidative phosphorylation to lactate production (Park & Jeoung, 2016) (Figure 1b).…”

“…Of the specific top‐listed differentially expressed genes, two upregulated genes, CX3CR1 and ARID5B , have been previously associated with atherosclerosis (Landsman et al, 2009; Liu et al, 2017). The chemokine receptor CX3CR1 promotes the migration of monocytes and macrophages to sites of atherosclerotic lesions and its expression correlates with age (Landsman et al, 2009; Metcalf et al, 2017).…”

“…ARID5B is a transcription factor known to promote the activation of lipogenesis‐related genes and to affect cell motility (Yamakawa et al, 2008). Furthermore, Liu et al (2017) describe a strong link between the knock‐down of ARID5B mRNA and the decreased expression of atherosclerosis‐promoting factors. Our analysis lends support to the earlier findings and strengthens the notion that these two proteins have atherogenic properties, as age is one of the major risk factors for atherosclerosis.…”

“…With age, monocytes are recruited to atherosclerotic lesions by using the CX3CR1 chemokine receptor (Tacke et al, 2007), which has higher expression in older persons (Metcalf et al, 2017). Furthermore, the transcription co‐activator ARID5B, which promotes the expression of proinflammatory markers, is upregulated in monocytes from old individuals (Liu et al, 2017). The age‐related mitochondrial dysregulation observed in many other cell types manifests itself in monocytes as a decrease in the maximal respiratory capacity (Pence & Yarbro, 2018).…”

The transcriptome of CMML monocytes is highly inflammatory and reflects leukemia-specific and age-related alterations

“…TET2 is the most commonly mutated CHIP gene and Tet2-deficient monocytes promote atherosclerosis in low-density lipoprotein receptor-deficient mice. 51,52 Liu and colleagues 53 used the Multiethnic Study of Atherosclerosis (MESA) cohort to establish Table 1. correlations between the transcriptional signature of monocytes and the risk of human atherosclerosis, as defined by carotid plaque burden and coronary artery calcification.…”