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

Yongmei Liu (), Lindsay M. Reynolds, Jingzhong Ding, Li Hou, Kurt Lohman, Tracey Young, Wei Cui, Zhiqing Huang, Carole Grenier, Ma Wan, Hendrik G. Stunnenberg, David Siscovick, Lifang Hou, Bruce M. Psaty, Stephen S. Rich, Jerome I. Rotter, Joel D. Kaufman, Gregory L. Burke, Susan Murphy, David R. Jacobs, Wendy Post, Ina Hoeschele, Douglas A. Bell, David Herrington, John S. Parks, Russell P. Tracy, Charles E. McCall and James H. Stein
Additional contact information
Yongmei Liu: Wake Forest School of Medicine
Lindsay M. Reynolds: Wake Forest School of Medicine
Jingzhong Ding: Wake Forest School of Medicine
Li Hou: Wake Forest School of Medicine
Kurt Lohman: Wake Forest School of Medicine
Tracey Young: Wake Forest School of Medicine
Wei Cui: Wake Forest School of Medicine
Zhiqing Huang: Duke University
Carole Grenier: Duke University
Ma Wan: National Institutes of Health
Hendrik G. Stunnenberg: Nijmegen Centre for Molecular Life Sciences (NCMLS)
David Siscovick: New York Academy of Medicine
Lifang Hou: Northwestern University Feinberg School of Medicine
Bruce M. Psaty: University of Washington
Stephen S. Rich: University of Virginia
Jerome I. Rotter: Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center
Joel D. Kaufman: University of Washington
Gregory L. Burke: Wake Forest School of Medicine
Susan Murphy: Duke University
David R. Jacobs: University of Minnesota
Wendy Post: Johns Hopkins University
Ina Hoeschele: Biocomplexity Institute and Department of Statistics
Douglas A. Bell: National Institutes of Health
David Herrington: Wake Forest School of Medicine
John S. Parks: Wake Forest School of Medicine
Russell P. Tracy: University of Vermont
Charles E. McCall: Wake Forest School of Medicine
James H. Stein: University of Wisconsin School of Medicine and Public Health

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00517-4

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