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Lipid-induced epigenomic changes in human macrophages identify a coronary artery disease-associated variant that regulates PPAP2B Expression through Altered C/EBP-beta binding.

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cam.issuedOnline2015-04-02
dc.contributor.authorReschen, Michael E
dc.contributor.authorGaulton, Kyle J
dc.contributor.authorLin, Da
dc.contributor.authorSoilleux, Elizabeth J
dc.contributor.authorMorris, Andrew J
dc.contributor.authorSmyth, Susan S
dc.contributor.authorO'Callaghan, Christopher A
dc.contributor.orcidSoilleux, Elizabeth [0000-0002-4032-7249]
dc.date.accessioned2018-12-18T00:33:07Z
dc.date.available2018-12-18T00:33:07Z
dc.date.issued2015-04
dc.description.abstractGenome-wide association studies (GWAS) have identified over 40 loci that affect risk of coronary artery disease (CAD) and the causal mechanisms at the majority of loci are unknown. Recent studies have suggested that many causal GWAS variants influence disease through altered transcriptional regulation in disease-relevant cell types. We explored changes in transcriptional regulation during a key pathophysiological event in CAD, the environmental lipid-induced transformation of macrophages to lipid-laden foam cells. We used a combination of open chromatin mapping with formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) and enhancer and transcription factor mapping using chromatin immuno-precipitation (ChIP-seq) in primary human macrophages before and after exposure to atherogenic oxidized low-density lipoprotein (oxLDL), with resultant foam cell formation. OxLDL-induced foam cell formation was associated with changes in a subset of open chromatin and active enhancer sites that strongly correlated with expression changes of nearby genes. OxLDL-regulated enhancers were enriched for several transcription factors including C/EBP-beta, which has no previously documented role in foam cell formation. OxLDL exposure up-regulated C/EBP-beta expression and increased genomic binding events, most prominently around genes involved in inflammatory response pathways. Variants at CAD-associated loci were significantly and specifically enriched in the subset of chromatin sites altered by oxLDL exposure, including rs72664324 in an oxLDL-induced enhancer at the PPAP2B locus. OxLDL increased C/EBP beta binding to this site and C/EBP beta binding and enhancer activity were stronger with the protective A allele of rs72664324. In addition, expression of the PPAP2B protein product LPP3 was present in foam cells in human atherosclerotic plaques and oxLDL exposure up-regulated LPP3 in macrophages resulting in increased degradation of pro-inflammatory mediators. Our results demonstrate a genetic mechanism contributing to CAD risk at the PPAP2B locus and highlight the value of studying epigenetic changes in disease processes involving pathogenic environmental stimuli.
dc.format.mediumElectronic-eCollection
dc.identifier.doi10.17863/CAM.34430
dc.identifier.eissn1553-7404
dc.identifier.issn1553-7390
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287121
dc.languageeng
dc.language.isoeng
dc.publisherPublic Library of Science (PLoS)
dc.publisher.urlhttp://dx.doi.org/10.1371/journal.pgen.1005061
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCCAAT-Enhancer-Binding Protein-beta
dc.subjectCells, Cultured
dc.subjectCoronary Artery Disease
dc.subjectEpigenesis, Genetic
dc.subjectFoam Cells
dc.subjectGenetic Loci
dc.subjectHumans
dc.subjectLipoproteins, LDL
dc.subjectPhosphatidate Phosphatase
dc.subjectPlaque, Atherosclerotic
dc.subjectPolymorphism, Single Nucleotide
dc.subjectProtein Binding
dc.titleLipid-induced epigenomic changes in human macrophages identify a coronary artery disease-associated variant that regulates PPAP2B Expression through Altered C/EBP-beta binding.
dc.typeArticle
dcterms.dateAccepted2015-02-09
prism.issueIdentifier4
prism.publicationDate2015
prism.publicationNamePLoS Genet
prism.startingPagee1005061
prism.volume11
rioxxterms.licenseref.startdate2015-04-02
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1371/journal.pgen.1005061

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