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Epigenetic memory of obesity in mouse colonic epithelium

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE85731 | GEO | 2017/12/19

SECONDARY ACCESSION(S): PRJNA339220

REPOSITORIES: GEO

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Project description:Colorectal cancer often arises from adenomatous polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Prediciting which progress to cancer and which remain benign is difficult. We developed a long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived Apcin/+ mice were treated with 4% dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy, and pathology was determined. Serial biopsies of tumors were obtained for immunohistochemistry and gene expression profiling by microarray analysis with Affymetrix Whole Genome array. Tumors (n=424) grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated dynamic growth patterns with higher rates of growth and resolution, while more established tumors tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Differentially expressed genes between adenomas and intramucosal carcinomas were identified. We did not identify differentially expressed genes between early and late biopsies from the same tumor. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features are needed to determine which features can be used to risk-stratify polyps for progress to colorectal cancer and potentially guide prevention strategies. F1 (SWR x C57BL/6) Apcin/+ mice who had been given two treatments of 4% dextran sodium sulfate in drinking water at weaning underwent colonoscopy around 80 days of age. Those with distal colonic tumors amenable to biopsy had two biopsies taken at that time. Tumors were monitored by colonoscopy every 14 days. Every 28 days, two additional biopsies were taken of each tumor. This protocol was repeated until mice were moribund. Six tumors were removed after sacrifice. The earliest and latest biopsies of each tumor were selected for RNA extraction and Affymetrix hybridization.

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Epigenetic memory of obesity in mouse colonic epithelium

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