Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer

Ruifang Li, Sara A. Grimm, Deepak Mav, Haiwei Gu, Danijel Djukovic, Ruchir Shah, B. Alex Merrick, Daniel Raftery, Paul A. Wade

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Colorectal cancer (CRC) tends to occur at older age; however, CRC incidence rates have been rising sharply among young age groups. The increasing prevalence of obesity is recognized as a major risk, yet the mechanistic underpinnings remain poorly understood. Using a diet-induced obesity mouse model, we identified obesity-associated molecular changes in the colonic epithelium of young and aged mice, and we further investigated whether the changes were reversed after weight loss. Transcriptome analysis indicated that obesity-related colonic cellular metabolic switch favoring long-chain fatty acid oxidation happened in young mice, while obesity-associated downregulation of negative feedback regulators of pro-proliferative signaling pathways occurred in older mice. Strikingly, colonic DNA methylome was pre-programmed by obesity at young age, priming for a tumor-prone gene signature after aging. Furthermore, obesity-related changes were substantially preserved after short-term weight loss, but they were largely reversed after long-term weight loss. We provided mechanistic insights into increased CRC risk in obesity. Li et al. find that obesity-induced DNA methylation changes reprogram the colonic transcriptome, leading to a metabolic switch favoring long-chain fatty acid oxidation in young mice and a more tumor-prone gene signature after aging. Obesity-related changes are substantially preserved after short-term weight loss, but they are largely reversed after long-term weight loss.

Original languageEnglish (US)
Pages (from-to)624-637
Number of pages14
JournalCell Reports
Volume22
Issue number3
DOIs
StatePublished - Jan 16 2018
Externally publishedYes

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Keywords

  • cellular metabolism
  • colorectal cancer
  • DNA methylation
  • gene expression
  • obesity
  • signal transduction
  • weight loss

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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