Epigenetic memory of obesity in mouse colonic epithelium

Colorectal cancer is the third most common cancer. Obesity is a major risk factor with long-lasting effects on the predisposition to colorectal cancer; however, the mechanistic underpinnings remain poorly understood. To explore epigenetic mechanisms involved, we performed whole-genome bisulfite sequencing and RNA-Seq in colonic epithelium from control mice, obese mice, and formerly obese mice. We found that obesity-induced DNA methylation changes reprogrammed the transcriptome leading to a metabolic switch favoring long chain fatty acid oxidation, which is essential to colonic stem cell functions and colon tumorigenesis. Remarkably, persistent changes were observed after weight loss mainly at metabolic and cancer-related genes, underlying the long-term predisposition to colorectal cancer. In summary, we provide the epigenetic and metabolic basis of the link between obesity and colorectal cancer. Whole-genome bisulfite sequencing, bisulfite PCR deep sequencing, and RNA-Seq were performed in colonic epithelium from mice on three different dietary regimens as follows: 1) low-fat diet for 20 weeks; 2) high-fat diet for 20 weeks; 3) high-fat diet for an initial 15 weeks then switched to low-fat diet for another 5 weeks.