title: Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis.
abstract: Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by 'genomic convergence' for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2'-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex disease.
authors.affiliation: Department of Medicine and Division of Cardiovascular Medicine and.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Connelly
authors.forename: Olga A
authors.initials: OA
authors.lastname: Cherepanova
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Doss
authors.forename: Themistoclis
authors.initials: T
authors.lastname: Karaoli
authors.forename: Travis S
authors.initials: TS
authors.lastname: Lillard
authors.forename: Christina A
authors.initials: CA
authors.lastname: Markunas
authors.forename: Sarah
authors.initials: S
authors.lastname: Nelson
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Wang
authors.forename: Peter D
authors.initials: PD
authors.lastname: Ellis
authors.forename: Cordelia F
authors.initials: CF
authors.lastname: Langford
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.forename: David M
authors.initials: DM
authors.lastname: Seo
authors.forename: Pascal J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
mesh_terms: D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D003094:Collagen / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D058426:Neointima / Q000235:genetics
chemical_list: C085811:COL15A1 protein, human; D003094:Collagen
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