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; James H. Stein

doi:10.1038/s41467-017-00517-4

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. JacobsWendy Post, Ina Hoeschele, Douglas A. Bell, David Herrington, John S. Parks, Russell P. Tracy, Charles E. McCall, James H. Stein

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	393
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00517-4
State	Published - Dec 1 2017

Funding

This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169, and R01 HL 119962 from the National Heart, Lung, and Blood Institute. The MESA Epigenomics and Transcriptomics Studies were funded by R01HL101250, R01 DK103531-01, R01 DK103531, R01 AG054474, and R01 HL135009-01 to Wake Forest University Health Sciences. The research described in this publication was funded in part by the U.S. Environmental Protection Agency through RD831697 to the University of Washington (MESA Air); it has not been subjected to the Agency’s required peer and policy review and therefore does not necessarily reflect the views of the Agency and no official endorsement should be inferred.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-017-00517-4

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Liu, Y., Reynolds, L. M., Ding, J., Hou, L., Lohman, K., Young, T., Cui, W., Huang, Z., Grenier, C., Wan, M., Stunnenberg, H. G., Siscovick, D., Hou, L., Psaty, B. M., Rich, S. S., Rotter, J. I., Kaufman, J. D., Burke, G. L., Murphy, S., ... Stein, J. H. (2017). Blood monocyte transcriptome and epigenome analyses reveal loci associated with human atherosclerosis. Nature communications, 8(1), Article 393. https://doi.org/10.1038/s41467-017-00517-4

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title = "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.",

author = "Yongmei Liu and Reynolds, {Lindsay M.} and Jingzhong Ding and Li Hou and Kurt Lohman and Tracey Young and Wei Cui and Zhiqing Huang and Carole Grenier and Ma Wan and Stunnenberg, {Hendrik G.} and David Siscovick and Lifang Hou and Psaty, {Bruce M.} and Rich, {Stephen S.} and Rotter, {Jerome I.} and Kaufman, {Joel D.} and Burke, {Gregory L.} and Susan Murphy and Jacobs, {David R.} and Wendy Post and Ina Hoeschele and Bell, {Douglas A.} and David Herrington and Parks, {John S.} and Tracy, {Russell P.} and McCall, {Charles E.} and Stein, {James H.}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00517-4",

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Liu, Y, Reynolds, LM, Ding, J, Hou, L, Lohman, K, Young, T, Cui, W, Huang, Z, Grenier, C, Wan, M, Stunnenberg, HG, Siscovick, D, Hou, L, Psaty, BM, Rich, SS, Rotter, JI, Kaufman, JD, Burke, GL, Murphy, S, Jacobs, DR, Post, W, Hoeschele, I, Bell, DA, Herrington, D, Parks, JS, Tracy, RP, McCall, CE & Stein, JH 2017, 'Blood monocyte transcriptome and epigenome analyses reveal loci associated with human atherosclerosis', Nature communications, vol. 8, no. 1, 393. https://doi.org/10.1038/s41467-017-00517-4

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T1 - Blood monocyte transcriptome and epigenome analyses reveal loci associated with human atherosclerosis

AU - Liu, Yongmei

AU - Reynolds, Lindsay M.

AU - Ding, Jingzhong

AU - Hou, Li

AU - Lohman, Kurt

AU - Young, Tracey

AU - Cui, Wei

AU - Huang, Zhiqing

AU - Grenier, Carole

AU - Wan, Ma

AU - Stunnenberg, Hendrik G.

AU - Siscovick, David

AU - Hou, Lifang

AU - Psaty, Bruce M.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Kaufman, Joel D.

AU - Burke, Gregory L.

AU - Murphy, Susan

AU - Jacobs, David R.

AU - Post, Wendy

AU - Hoeschele, Ina

AU - Bell, Douglas A.

AU - Herrington, David

AU - Parks, John S.

AU - Tracy, Russell P.

AU - McCall, Charles E.

AU - Stein, James H.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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JO - Nature communications

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M1 - 393

ER -

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

Abstract

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ASJC Scopus subject areas

UN SDGs

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