Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis

Jessica J. Connelly, Olga A. Cherepanova, Jennifer F. Doss, Themistoclis Karaoli, Travis S. Lillard, Christina A. Markunas, Sarah Nelson, Tianyuan Wang, Peter D. Ellis, Cordelia F. Langford, Carol Haynes, David M Seo, Pascal Goldschmidt-Clermont, Svati H. Shah, William E. Kraus, Elizabeth R. Hauser, Simon G. Gregory

Research output: Contribution to journalArticle

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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 programmedor stochastic nature of hypomethylation, identifyingthesechanges is important in understanding vascular disease,asmaintenance ofacells' epigenetic profile is essential for maintaining cellularphenotype. Global hypomethylation of proliferating aorticSMCsandconcomitant decrease ofDNMT1 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 5 0.017, OR 5 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.

Original languageEnglish
Article numberddt365
Pages (from-to)5107-5120
Number of pages14
JournalHuman Molecular Genetics
Volume22
Issue number25
DOIs
StatePublished - Dec 1 2013

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Cell Aging
Epigenomics
Smooth Muscle Myocytes
Atherosclerosis
decitabine
Cell Proliferation
DNA Methylation
Genetic Predisposition to Disease
Vascular Diseases
Gene Expression
Vascular System Injuries
Methylation
Cell Movement
Aorta
Collagen
Alleles
Genome
Phenotype
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Connelly, J. J., Cherepanova, O. A., Doss, J. F., Karaoli, T., Lillard, T. S., Markunas, C. A., ... Gregory, S. G. (2013). Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis. Human Molecular Genetics, 22(25), 5107-5120. [ddt365]. https://doi.org/10.1093/hmg/ddt365

Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis. / Connelly, Jessica J.; Cherepanova, Olga A.; Doss, Jennifer F.; Karaoli, Themistoclis; Lillard, Travis S.; Markunas, Christina A.; Nelson, Sarah; Wang, Tianyuan; Ellis, Peter D.; Langford, Cordelia F.; Haynes, Carol; Seo, David M; Goldschmidt-Clermont, Pascal; Shah, Svati H.; Kraus, William E.; Hauser, Elizabeth R.; Gregory, Simon G.

In: Human Molecular Genetics, Vol. 22, No. 25, ddt365, 01.12.2013, p. 5107-5120.

Research output: Contribution to journalArticle

Connelly, JJ, Cherepanova, OA, Doss, JF, Karaoli, T, Lillard, TS, Markunas, CA, Nelson, S, Wang, T, Ellis, PD, Langford, CF, Haynes, C, Seo, DM, Goldschmidt-Clermont, P, Shah, SH, Kraus, WE, Hauser, ER & Gregory, SG 2013, 'Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis', Human Molecular Genetics, vol. 22, no. 25, ddt365, pp. 5107-5120. https://doi.org/10.1093/hmg/ddt365
Connelly JJ, Cherepanova OA, Doss JF, Karaoli T, Lillard TS, Markunas CA et al. Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis. Human Molecular Genetics. 2013 Dec 1;22(25):5107-5120. ddt365. https://doi.org/10.1093/hmg/ddt365
Connelly, Jessica J. ; Cherepanova, Olga A. ; Doss, Jennifer F. ; Karaoli, Themistoclis ; Lillard, Travis S. ; Markunas, Christina A. ; Nelson, Sarah ; Wang, Tianyuan ; Ellis, Peter D. ; Langford, Cordelia F. ; Haynes, Carol ; Seo, David M ; Goldschmidt-Clermont, Pascal ; Shah, Svati H. ; Kraus, William E. ; Hauser, Elizabeth R. ; Gregory, Simon G. / Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 25. pp. 5107-5120.
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