title: Methylation kinetics and CpG-island methylator phenotype status in colorectal cancer cell lines.
abstract: BACKGROUND
  Hypermethylation of CpG islands is thought to contribute to carcinogenesis through the inactivation of tumor suppressor genes. Tumor cells with relatively high levels of CpG island methylation are considered CpG island methylator phenotypes (CIMP). The mechanisms that are responsible for regulating the activity of de novo methylation are not well understood.
  
  
  RESULTS
  We quantify and compare de novo methylation kinetics in CIMP and non-CIMP colon cancer cell lines in the context of different loci, following 5-aza-2'deoxycytidine (5-AZA)-mediated de-methylation of cells. In non-CIMP cells, a relatively fast rate of re-methylation is observed that starts with a certain time delay after cessation of 5-AZA treatment. CIMP cells, on the other hand, start re-methylation without a time delay but at a significantly slower rate. A mathematical model can account for these counter-intuitive results by assuming negative feedback regulation of de novo methylation activity and by further assuming that this regulation is corrupted in CIMP cells. This model further suggests that when methylation levels have grown back to physiological levels, de novo methylation activity ceases in non-CIMP cells, while it continues at a constant low level in CIMP cells.
  
  
  CONCLUSIONS
  We propose that the faster rate of re-methylation observed in non-CIMP compared to CIMP cells in our study could be a consequence of feedback-mediated regulation of DNA methyl transferase activity. Testing this hypothesis will involve the search for specific feedback regulatory mechanisms involved in the activation of de novo methylation.
  This article was reviewed by Georg Luebeck, Tomasz Lipniacki, and Anna Marciniak-Czochra.
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Irvine, CA 92697, USA.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wodarz
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.forename: Natalia L
authors.initials: NL
authors.lastname: Komarova
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008962:Models, Theoretical