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

9 Citations (Scopus)

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

Fingerprint

Nutrition
Transcriptome
Colorectal Neoplasms
Obesity
Diet
DNA
Weight Loss
Tumors
Fatty Acids
Genes
Aging of materials
Switches
Oxidation
Feedback
Gene Expression Profiling
DNA Methylation
Neoplasms
Down-Regulation
Epithelium
Age Groups

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer. / Li, Ruifang; Grimm, Sara A.; Mav, Deepak; Gu, Haiwei; Djukovic, Danijel; Shah, Ruchir; Merrick, B. Alex; Raftery, Daniel; Wade, Paul A.

In: Cell Reports, Vol. 22, No. 3, 16.01.2018, p. 624-637.

Research output: Contribution to journalArticle

Li, Ruifang ; Grimm, Sara A. ; Mav, Deepak ; Gu, Haiwei ; Djukovic, Danijel ; Shah, Ruchir ; Merrick, B. Alex ; Raftery, Daniel ; Wade, Paul A. / Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer. In: Cell Reports. 2018 ; Vol. 22, No. 3. pp. 624-637.
@article{05831bb486524bd0818734b8b0ece1cb,
title = "Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer",
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.",
keywords = "cellular metabolism, colorectal cancer, DNA methylation, gene expression, obesity, signal transduction, weight loss",
author = "Ruifang Li and Grimm, {Sara A.} and Deepak Mav and Haiwei Gu and Danijel Djukovic and Ruchir Shah and Merrick, {B. Alex} and Daniel Raftery and Wade, {Paul A.}",
year = "2018",
month = "1",
day = "16",
doi = "10.1016/j.celrep.2017.12.071",
language = "English (US)",
volume = "22",
pages = "624--637",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer

AU - Li, Ruifang

AU - Grimm, Sara A.

AU - Mav, Deepak

AU - Gu, Haiwei

AU - Djukovic, Danijel

AU - Shah, Ruchir

AU - Merrick, B. Alex

AU - Raftery, Daniel

AU - Wade, Paul A.

PY - 2018/1/16

Y1 - 2018/1/16

N2 - 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.

AB - 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.

KW - cellular metabolism

KW - colorectal cancer

KW - DNA methylation

KW - gene expression

KW - obesity

KW - signal transduction

KW - weight loss

UR - http://www.scopus.com/inward/record.url?scp=85041643767&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041643767&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2017.12.071

DO - 10.1016/j.celrep.2017.12.071

M3 - Article

VL - 22

SP - 624

EP - 637

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 3

ER -