TitleEpigenome-guided analysis of the transcriptome of plaque macrophages during atherosclerosis regression reveals activation of the Wnt signaling pathway.
Publication TypeJournal Article
Year of Publication2014
AuthorsRamsey, SA, Vengrenyuk, Y, Menon, P, Podolsky, I, Feig, JE, Aderem, A, Fisher, EA, Gold, ES
JournalPLoS Genet
Volume10
Issue12
Paginatione1004828
Date Published2014 Dec
ISSN1553-7404
KeywordsAnimals, Cells, Cultured, Epigenesis, Genetic, Female, Gene Expression Profiling, Genome, Hypolipidemic Agents, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Microarray Analysis, Plaque, Atherosclerotic, Receptors, LDL, Remission Induction, Transcriptome, Wnt Signaling Pathway
Abstract

We report the first systems biology investigation of regulators controlling arterial plaque macrophage transcriptional changes in response to lipid lowering in vivo in two distinct mouse models of atherosclerosis regression. Transcriptome measurements from plaque macrophages from the Reversa mouse were integrated with measurements from an aortic transplant-based mouse model of plaque regression. Functional relevance of the genes detected as differentially expressed in plaque macrophages in response to lipid lowering in vivo was assessed through analysis of gene functional annotations, overlap with in vitro foam cell studies, and overlap of associated eQTLs with human atherosclerosis/CAD risk SNPs. To identify transcription factors that control plaque macrophage responses to lipid lowering in vivo, we used an integrative strategy--leveraging macrophage epigenomic measurements--to detect enrichment of transcription factor binding sites upstream of genes that are differentially expressed in plaque macrophages during regression. The integrated analysis uncovered eight transcription factor binding site elements that were statistically overrepresented within the 5' regulatory regions of genes that were upregulated in plaque macrophages in the Reversa model under maximal regression conditions and within the 5' regulatory regions of genes that were upregulated in the aortic transplant model during regression. Of these, the TCF/LEF binding site was present in promoters of upregulated genes related to cell motility, suggesting that the canonical Wnt signaling pathway may be activated in plaque macrophages during regression. We validated this network-based prediction by demonstrating that β-catenin expression is higher in regressing (vs. control group) plaques in both regression models, and we further demonstrated that stimulation of canonical Wnt signaling increases macrophage migration in vitro. These results suggest involvement of canonical Wnt signaling in macrophage emigration from the plaque during lipid lowering-induced regression, and they illustrate the discovery potential of an epigenome-guided, systems approach to understanding atherosclerosis regression.

DOI10.1371/journal.pgen.1004828
Alternate JournalPLoS Genet
PubMed ID25474352
PubMed Central IDPMC4256277
Grant ListR01HL084312 / HL / NHLBI NIH HHS / United States
R01 AI032972 / AI / NIAID NIH HHS / United States
F30 AG029748 / AG / NIA NIH HHS / United States
T32HL098129 / HL / NHLBI NIH HHS / United States
R01AI032972 / AI / NIAID NIH HHS / United States
T32 HL098129 / HL / NHLBI NIH HHS / United States
U19 AI100627 / AI / NIAID NIH HHS / United States
F30AG029748 / AG / NIA NIH HHS / United States
R01AI025032 / AI / NIAID NIH HHS / United States
R01 AI025032 / AI / NIAID NIH HHS / United States
U19AI100627 / AI / NIAID NIH HHS / United States
K25HL098807 / HL / NHLBI NIH HHS / United States
R01 HL084312 / HL / NHLBI NIH HHS / United States
K25 HL098807 / HL / NHLBI NIH HHS / United States