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Title:Epigenetics, a signal sensor of dietary components, is involved in the hepatic gene regulation
Author(s):Zhou, Dan
Director of Research:Pan, Yuan-Xiang
Doctoral Committee Chair(s):Helferich, William G.
Doctoral Committee Member(s):Pan, Yuan-Xiang; Engeseth, Nicki J.; Chen, Hong
Department / Program:Food Science & Human Nutrition
Discipline:Food Science & Human Nutrition
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):high fat diet
maternal programming
Cyclooxygenase-2 (COX-2)
Methylated DNA immunoprecipitation (MeDIP)
Abstract:Epigenetic markers are associated with a broad range of disease symptoms, including cancer, asthma, metabolic disorders, and various reproductive conditions. Changes in epigenetics status could be induced by environmental exposures such as malnutrition, stress, smoking, disease and exposure to air pollutants and organic chemicals. Dietary factors were extensively acknowledged to be one of the key environmental essences affecting chromatin structure. It can diversify the patterns of DNA methylation and histone modifications. The changes may be pathogenic and result in severe physiological consequences, particularly if the exposure occurs during critical window of development. This is potentially attributable to the property of epigenetic activities, which occurs not only in somatic and mitotic cells, but also inherited meiotically, meaning that the changes are carried over generations [1, 2]. Therefore, maternal dietary factors may profoundly characterize the phenotype of subsequent generations and consequently contribute to the early onset of chronic disease and metabolic disorder [3]. Sustained high fat feeding leads to obesity and metabolic syndrome, accompanied by low-grade inflammation, insulin resistance, and dyslipidemia. In general, the prevalence of an inflammatory response is highly associated with obesity incidence, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD) and brain damage. In liver, changes caused by low-grade inflammation may later result in progressive disease and fibrosis. Early exposure to a fat-enriched diet programs the developmental profile, thus is associated with disease susceptibility in subsequent generations. Chronic low-grade inflammation, resulting from high fat diet, is activated in the fetal environment and in many organs of offspring, including placenta, adipose, liver, vascular system and brain. It forms the biological basis for many patho-physiological changes and constitutes risk factors for disease development. Chronic inflammatory disorders were recently identified as one of the major targets of dietary-induced epigenetic regulation [4]. Although some transgenerational effects of high dietary fat intake have been shown in a couple of studies linked to certain types of epigenetic modulations [5-8]; these modifications and their associated physiological consequences resulting from high fat induced-chronic inflammation remain elusive. Should the MHF-resulted epigenetic code persist throughout generations, characterization in such situations may favor the prediction, early prevention, and treatment of non-communicable disease in next few generations [9]. Many studies using high fat models have consistently demonstrated the incidence of such inflammatory reactions. However, the potential contributions of epigenetic modifications toward the regulation of inflammatory genes and subsequent physiological outcomes have not been fully revealed in the high fat feeding model. Cyclooxygenase-2 (COX-2) produces prostaglandins that participate in multiple physiological and pathological processes, including the activation of inflammatory responses. In addition to many of the transcription factors known for years, it was recently suggested that COX-2 expression is also subjected to epigenetic modifications, either through histone remodeling and/or DNA methylation [10]. Therefore, our study aims to investigate the epigenetic mechanisms by which consumption of a high fat diet at different life stages influences the inflammatory marker COX-2. Male Sprague-Dawley rats received a high fat diet at different life stages, including maternal (HF/C), post-weaning (C/HF), and lifelong (HF/HF). Liver was collected for analysis at 12 weeks of age. Results showed that the high fat diet induced the expression of COX-2 mRNA in all three high fat groups. RNA abundance of COX-2 in HF/HF was significantly higher than that of HF/C and C/HF. Meanwhile, fatty acid composition showed that the proportion of Linoleic acid and Arachidonic acid, as well as Δ6Desaturase, were significantly increased in high fat groups, potentially motivating the biochemical flow as well as providing reaction substrate for COX-2 catalysis. Genome-wide methylated DNA immunoprecipitation (MeDIP) showed that DNA hypomethylation occurred in an upstream region of the distal promoter and two coding regions of the COX-2 gene in all three high fat groups. Site-specific hypomethylation of CpG at 5’ UTR (untranslated region) of COX-2 was confirmed with bisulfite sequencing. Using in vitro cloning and Luciferase Reporter assay, this region was identified as a novel enhancer that produces durable transcriptional activity. In conclusion, high fat intake during different life stages resulted in a varied induction level of COX-2 gene expression. Altered DNA methylation at specific gene region, including the 5’UTR enhancer sequence, may closely associate with COX-2 gene activation. This study presented a gene-wide illustration of the diet-epigenome interaction. It also provided evidence of high fat diet-induced region-specific hypomethylation in the liver of the offspring. Since limited research has been conducted to reveal the epigenetic regulation of inflammatory markers by high fat diet, this study will not only outline the dietary outcomes on the epigenetic profile of a specific inflammatory gene, but also provide insight for future mechanistic investigation and clinical appliance in the area of epigenetics.
Issue Date:2014-05-30
Rights Information:Copyright 2014 Dan Zhou
Date Available in IDEALS:2014-05-30
Date Deposited:2014-05

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