Skip to main content
Journal cover image

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

Publication ,  Journal Article
Connelly, JJ; Cherepanova, OA; Doss, JF; Karaoli, T; Lillard, TS; Markunas, CA; Nelson, S; Wang, T; Ellis, PD; Langford, CF; Haynes, C ...
Published in: Hum Mol Genet
December 20, 2013

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

December 20, 2013

Volume

22

Issue

25

Start / End Page

5107 / 5120

Location

England

Related Subject Headings

  • Neointima
  • Myocytes, Smooth Muscle
  • Humans
  • Genetics & Heredity
  • Gene Expression Regulation
  • Epigenesis, Genetic
  • DNA Methylation
  • Collagen
  • Cellular Senescence
  • Cells, Cultured
 

Citation

APA
Chicago
ICMJE
MLA
NLM
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. Hum Mol Genet, 22(25), 5107–5120. https://doi.org/10.1093/hmg/ddt365
Connelly, Jessica J., Olga A. Cherepanova, Jennifer F. Doss, Themistoclis Karaoli, Travis S. Lillard, Christina A. Markunas, Sarah Nelson, et al. “Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis.Hum Mol Genet 22, no. 25 (December 20, 2013): 5107–20. 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. Hum Mol Genet. 2013 Dec 20;22(25):5107–20.
Connelly, Jessica J., et al. “Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis.Hum Mol Genet, vol. 22, no. 25, Dec. 2013, pp. 5107–20. Pubmed, doi:10.1093/hmg/ddt365.
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 PJ, Shah SH, Kraus WE, Hauser ER, Gregory SG. Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis. Hum Mol Genet. 2013 Dec 20;22(25):5107–5120.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

December 20, 2013

Volume

22

Issue

25

Start / End Page

5107 / 5120

Location

England

Related Subject Headings

  • Neointima
  • Myocytes, Smooth Muscle
  • Humans
  • Genetics & Heredity
  • Gene Expression Regulation
  • Epigenesis, Genetic
  • DNA Methylation
  • Collagen
  • Cellular Senescence
  • Cells, Cultured