title: Epigenome-guided analysis of the transcriptome of plaque macrophages during atherosclerosis regression reveals activation of the 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.
authors.affiliation: Department of Biomedical Sciences and School of Electrical Engineering and Computer Science, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ramsey
authors.affiliation: Division of Cardiology, School of Medicine, New York University, New York, New York, United States of America.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Vengrenyuk
authors.affiliation: Division of Cardiology, School of Medicine, New York University, New York, New York, United States of America.
authors.forename: Prashanthi
authors.initials: P
authors.lastname: Menon
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Irina
authors.initials: I
authors.lastname: Podolsky
authors.affiliation: Division of Cardiology, School of Medicine, New York University, New York, New York, United States of America.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Feig
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.affiliation: Division of Cardiology, School of Medicine, New York University, New York, New York, United States of America.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Gold
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D016678:Genome / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000235:genetics; D012074:Remission Induction; D059467:Transcriptome / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics
chemical_list: D000960:Hypolipidemic Agents; D011973:Receptors, LDL