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Browsing by Author "Siscovick, David"

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    Age-related variations in the methylome associated with gene expression in human monocytes and T cells
    Reynolds, Lindsay M.; Taylor, Jackson R.; Ding, Jingzhong; Lohman, Kurt; Johnson, Craig; Siscovick, David; Burke, Gregory L.; Post, Wendy; Shea, Steven; Jacobs, David R. Jr.; Stunnenberg, Hendrik G.; Kritchevsky, Stephen B.; Hoeschele, Ina; McCall, Charles E.; Herrington, David M.; Tracy, Russell P.; Liu, Yongmei (Springer Nature, 2014-11)
    Age-related variations in DNA methylation have been reported; however, the functional relevance of these differentially methylated sites (age-dMS) are unclear. Here we report potentially functional age-dMS, defined as age-and cis-gene expression-associated methylation sites (age-eMS), identified by integrating genome-wide CpG methylation and gene expression profiles collected ex vivo from circulating T cells (227 CD4+ samples) and monocytes (1,264 CD14+ samples, age range: 55-94 years). None of the age-eMS detected in 227 T-cell samples are detectable in 1,264 monocyte samples, in contrast to the majority of age-dMS detected in T cells that replicated in monocytes. Age-eMS tend to be hypomethylated with older age, located in predicted enhancers and preferentially linked to expression of antigen processing and presentation genes. These results identify and characterize potentially functional age-related methylation in human T cells and monocytes, and provide novel insights into the role age-dMS may have in the aging process.
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    Blood monocyte transcriptome and epigenome analyses reveal loci associated with human atherosclerosis
    Liu, Yongmei; Reynolds, Lindsay M.; Ding, Jingzhong; Hou, Li; Lohman, Kurt; Young, Tracey; Cui, Wei; Huang, Zhiqing; Grenier, Carole; Wan, Ma; Stunnenberg, Hendrik G.; Siscovick, David; Hou, Lifang; Psaty, Bruce M.; Rich, Stephen S.; Rotter, Jerome I.; Kaufman, Joel D.; Burke, Gregory L.; Murphy, Susan F.; Jacobs, David R. Jr.; Post, Wendy; Hoeschele, Ina; Bell, Douglas A.; Herrington, David M.; Parks, John S.; Tracy, Russell P.; McCall, Charles E.; Stein, James H. (Springer Nature, 2017-08-30)
    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.