Increasing evidences demonstrate that adapting to different environmental conditions is mediated by epigenetic changes, which can participate in cellular processes. In particular, the adaptation to the different caloric intakes is of great relevance as it is crucial for the organism’s fitness. Moreover, the phenotypic remodeling induced by different diets determine the susceptibility to life-threatening diseases. For example, refined sugar, fat and meat enriched diet, typical of Western countries, is thought to be responsible for about 30-35% of cancer cases, in addition to increased incidence of type 2 diabetes and cardiovascular diseases. On the other hand, caloric restriction has been shown to be the most powerful way to prolong lifespan and reduce cancer incidence in different experimental models. Based on the hypothesis that epigenetic changes represents the mechanistic link between diet and disease risk, the aim of this work is to investigate chromatin modifications induced by different diets in murine models to identify specific epigenetic profiles associated with fat enriched diets and caloric restriction. For this purpose, 8 weeks old C57Bl/6 female mice were divided in three groups and fed for 10 months with 3 different diets: Standard laboratory mouse Diet, Calorie Restriction without malnutrition, High Fat Diet. Then, livers were extracted and investigated by chromatin immunoprecipitation (anti-H3K4me3, anti-H3K27me3) and transcriptomic approach for gene expression analysis. Despite the presence of moderate technical and biological variability, data analysis demonstrated that specific epigenetic profiles were associated to different diets. In particular, the distribution and frequency of H3K4me3 enabled the clustering of samples by diet-group. Moreover, functional annotation of genes showing an increased signal of H3K4me3 for HF or CR respect to SD on their promoter regions, resulted in significantly enriched “Type II diabetes mellitus”, for which obesity represents a critical risk factor, and “Circadian Rhythm” pathways, whose known to affect longevity. At mechanistic level, two DNA motifs related to the transcription and chromatin regulators ZSCAN4 and REST/NRSF were found enriched in correspondence of the regulative regions of the genes of the aforementioned pathways, suggesting these factors mediate the effects of diet on chromatin and gene expression.

DIET-SPECIFIC EPIGENETIC SIGNATURE REVEALED BY H3K4ME3 AND H3K27ME3 DATA ANALYSIS IN C57BL6 MICE / A. Russo ; tutor: L. Luzi, M. Giorgio ; advisors: C. Furlanello, M. Vingron. - : . DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2016 Mar 18. ((27. ciclo, Anno Accademico 2015. [10.13130/russo-anna_phd2016-03-18].

DIET-SPECIFIC EPIGENETIC SIGNATURE REVEALED BY H3K4ME3 AND H3K27ME3 DATA ANALYSIS IN C57BL6 MICE

A. Russo
2016-03-18

Abstract

Increasing evidences demonstrate that adapting to different environmental conditions is mediated by epigenetic changes, which can participate in cellular processes. In particular, the adaptation to the different caloric intakes is of great relevance as it is crucial for the organism’s fitness. Moreover, the phenotypic remodeling induced by different diets determine the susceptibility to life-threatening diseases. For example, refined sugar, fat and meat enriched diet, typical of Western countries, is thought to be responsible for about 30-35% of cancer cases, in addition to increased incidence of type 2 diabetes and cardiovascular diseases. On the other hand, caloric restriction has been shown to be the most powerful way to prolong lifespan and reduce cancer incidence in different experimental models. Based on the hypothesis that epigenetic changes represents the mechanistic link between diet and disease risk, the aim of this work is to investigate chromatin modifications induced by different diets in murine models to identify specific epigenetic profiles associated with fat enriched diets and caloric restriction. For this purpose, 8 weeks old C57Bl/6 female mice were divided in three groups and fed for 10 months with 3 different diets: Standard laboratory mouse Diet, Calorie Restriction without malnutrition, High Fat Diet. Then, livers were extracted and investigated by chromatin immunoprecipitation (anti-H3K4me3, anti-H3K27me3) and transcriptomic approach for gene expression analysis. Despite the presence of moderate technical and biological variability, data analysis demonstrated that specific epigenetic profiles were associated to different diets. In particular, the distribution and frequency of H3K4me3 enabled the clustering of samples by diet-group. Moreover, functional annotation of genes showing an increased signal of H3K4me3 for HF or CR respect to SD on their promoter regions, resulted in significantly enriched “Type II diabetes mellitus”, for which obesity represents a critical risk factor, and “Circadian Rhythm” pathways, whose known to affect longevity. At mechanistic level, two DNA motifs related to the transcription and chromatin regulators ZSCAN4 and REST/NRSF were found enriched in correspondence of the regulative regions of the genes of the aforementioned pathways, suggesting these factors mediate the effects of diet on chromatin and gene expression.
PELICCI, PIER GIUSEPPE
PELICCI, PIER GIUSEPPE
Epigenetics; Diet; NGS; Histone Modifications; Bioinformatics
Settore BIO/11 - Biologia Molecolare
DIET-SPECIFIC EPIGENETIC SIGNATURE REVEALED BY H3K4ME3 AND H3K27ME3 DATA ANALYSIS IN C57BL6 MICE / A. Russo ; tutor: L. Luzi, M. Giorgio ; advisors: C. Furlanello, M. Vingron. - : . DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2016 Mar 18. ((27. ciclo, Anno Accademico 2015. [10.13130/russo-anna_phd2016-03-18].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/365343
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