title: High fat diet and exercise lead to a disrupted and pathogenic DNA methylome in mouse liver.
abstract: High-fat diet consumption and sedentary lifestyle elevates risk for obesity, non-alcoholic fatty liver disease, and cancer. Exercise training conveys health benefits in populations with or without these chronic conditions. Diet and exercise regulate gene expression by mediating epigenetic mechanisms in many tissues; however, such effects are poorly documented in the liver, a central metabolic organ. To dissect the consequences of diet and exercise on the liver epigenome, we measured DNA methylation, using reduced representation bisulfite sequencing, and transcription, using RNA-seq, in mice maintained on a fast food diet with sedentary lifestyle or exercise, compared with control diet with and without exercise. Our analyses reveal that genome-wide differential DNA methylation and expression of gene clusters are induced by diet and/or exercise. A combination of fast food and exercise triggers extensive gene alterations, with enrichment of carbohydrate/lipid metabolic pathways and muscle developmental processes. Through evaluation of putative protective effects of exercise on diet-induced DNA methylation, we show that hypermethylation is effectively prevented, especially at promoters and enhancers, whereas hypomethylation is only partially attenuated. We assessed diet-induced DNA methylation changes associated with liver cancer-related epigenetic modifications and identified significant increases at liver-specific enhancers in fast food groups, suggesting partial loss of liver cell identity. Hypermethylation at a subset of gene promoters was associated with inhibition of tissue development and promotion of carcinogenic processes. Our study demonstrates extensive reprogramming of the epigenome by diet and exercise, emphasizing the functional relevance of epigenetic mechanisms as an interface between lifestyle modifications and phenotypic alterations.
authors.affiliation: a Department of Molecular Pharmacology and Experimental Therapeutics , Mayo Clinic , Rochester , MN , USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.affiliation: a Department of Molecular Pharmacology and Experimental Therapeutics , Mayo Clinic , Rochester , MN , USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Hlady
authors.affiliation: b Robert and Arlene Kogod Center on Aging, Mayo Clinic , Rochester , MN , USA.|c Department of Physical Medicine & Rehabilitation , Mayo Clinic , Rochester , MN , USA.
authors.forename: Marissa J
authors.initials: MJ
authors.lastname: Schafer
authors.affiliation: b Robert and Arlene Kogod Center on Aging, Mayo Clinic , Rochester , MN , USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.affiliation: d Department of Pathology and Laboratory Medicine , Rutgers University , NJ , USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: e Department of Applied Research , Marine Biodiversity Institute of Korea , Korea.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: b Robert and Arlene Kogod Center on Aging, Mayo Clinic , Rochester , MN , USA.|f Department of Surgery , Mayo Clinic , Rochester , MN , USA.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Miller
authors.affiliation: g Mayo Clinic Cancer Center , Mayo Clinic , Rochester , MN , USA.|h Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester , MN , USA.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: b Robert and Arlene Kogod Center on Aging, Mayo Clinic , Rochester , MN , USA.|c Department of Physical Medicine & Rehabilitation , Mayo Clinic , Rochester , MN , USA.
authors.forename: Nathan K
authors.initials: NK
authors.lastname: LeBrasseur
authors.affiliation: a Department of Molecular Pharmacology and Experimental Therapeutics , Mayo Clinic , Rochester , MN , USA.|g Mayo Clinic Cancer Center , Mayo Clinic , Rochester , MN , USA.|i Center for Individualized Medicine, Mayo Clinic , Rochester , MN , USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Robertson
mesh_terms: D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D019175:DNA Methylation; D059305:Diet, High-Fat; D044127:Epigenesis, Genetic; D005247:Feeding Behavior / Q000502:physiology; D020869:Gene Expression Profiling; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010805:Physical Conditioning, Animal / Q000502:physiology*
keywords: Aging; DNA methylation; NAFLD; cancer; exercise; high fat