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

Epidemiology & Community Health

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

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© 2017 The Author(s).

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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

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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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.",

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AU - Cui, Wei

AU - Huang, Zhiqing

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AU - Stunnenberg, Hendrik G.

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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.

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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.

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

Abstract

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