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 Jr; Wendy Post; Ina Hoeschele; Douglas A Bell; David Herrington; John S Parks; Russell P Tracy; Charles E McCall; James H Stein

doi:10.1038/s41467-017-00517-4

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

Nat Commun. 2017 Aug 30;8(1):393. doi: 10.1038/s41467-017-00517-4.

Authors

Yongmei Liu¹, Lindsay M Reynolds², Jingzhong Ding³, Li Hou², Kurt Lohman⁴, Tracey Young², Wei Cui³, Zhiqing Huang⁵, Carole Grenier⁵, Ma Wan⁶, Hendrik G Stunnenberg⁷, David Siscovick⁸, Lifang Hou⁹, Bruce M Psaty^{10

11}, Stephen S Rich¹², Jerome I Rotter¹³, Joel D Kaufman¹⁴, Gregory L Burke², Susan Murphy⁵, David R Jacobs Jr¹⁵, Wendy Post¹⁶, Ina Hoeschele¹⁷, Douglas A Bell⁶, David Herrington³, John S Parks¹⁸, Russell P Tracy¹⁹, Charles E McCall¹⁸, James H Stein²⁰

Affiliations

¹ Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. yoliu@wakehealth.edu.
² Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
³ Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
⁴ Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
⁵ Duke University, Durham, NC, 27708, USA.
⁶ National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
⁷ Department of Molecular Biology, Nijmegen Centre for Molecular Life Sciences (NCMLS), 6525, GA, Nijmegen, The Netherlands.
⁸ New York Academy of Medicine, New York, NY, 10029, USA.
⁹ Division of Cancer Epidemiology and Prevention, Northwestern University Feinberg School of Medicine, Chicago, IL, 60208, USA.
¹⁰ Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, 98101, USA.
¹¹ Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA.
¹² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA.
¹³ Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
¹⁴ Department of Environmental and Occupational Health Sciences, Medicine and Epidemiology, University of Washington, Seattle, WA, 98104, USA.
¹⁵ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, 55455, USA.
¹⁶ Department of Pathology and Cardiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
¹⁷ Biocomplexity Institute and Department of Statistics, Virginia Tech, VA, 24061, USA.
¹⁸ Department of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
¹⁹ Department of Pathology, University of Vermont, Colchester, VT, 05446, USA.
²⁰ University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792, USA.

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.The molecular mechanisms mediating the impact of environmental factors in atherosclerosis are unclear. Here, the authors examine CD14+ blood monocyte's transcriptome and epigenome signatures to find differential methylation and expression of ARID5B to be associated with human atherosclerosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Atherosclerosis / genetics*
Atherosclerosis / metabolism
DNA Methylation
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Epigenesis, Genetic
Female
Histones / genetics
Histones / metabolism
Humans
Male
Middle Aged
Monocytes / chemistry
Monocytes / metabolism*
Transcription Factors / genetics*
Transcription Factors / metabolism
Transcriptome*

Substances

ARID5B protein, human
DNA-Binding Proteins
Histones
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding