Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression.
While obesity represents one of several risk factors for colorectal cancer in humans, the mechanistic underpinnings of this association remain unresolved. Environmental stimuli, including diet, can alter the epigenetic landscape of DNA cis-regulatory elements affecting gene expression and phenotype. Here, we explored the impact of diet and obesity on gene expression and the enhancer landscape in murine colonic epithelium. Obesity led to the accumulation of histone modifications associated with active enhancers at genomic loci downstream of signaling pathways integral to the initiation and progression of colon cancer. Meanwhile, colon-specific enhancers lost the same histone mark, poising cells for loss of differentiation. These alterations reflect a transcriptional program with many features shared with the program driving colon cancer progression. The interrogation of enhancer alterations by diet in colonic epithelium provides insights into the biology underlying high-fat diet and obesity as risk factors for colon cancer.
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Ruifang
R
Li
Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Sara A
SA
Grimm
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Kaliopi
K
Chrysovergis
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Justin
J
Kosak
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Xingya
X
Wang
Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Ying
Y
Du
Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Adam
A
Burkholder
ILS, Inc and Cellular and Molecular Pathology, DNTP, Research Triangle Park, NC 27709, USA.
Kyathanahalli
K
Janardhan
SRA International, Inc., Durham, NC 27709, USA.
Deepak
D
Mav
SRA International, Inc., Durham, NC 27709, USA.
Ruchir
R
Shah
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Thomas E
TE
Eling
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. Electronic address: wadep2@niehs.nih.gov.
Paul A
PA
Wade
D000818:Animals; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology
D006657:Histones