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Comparative Analysis of Histone H3k4me3 Distribution in Mouse Liver in Different Diets Reveals the Epigenetic Efficacy of Cyanidin-3-O-Glucoside Dietary Intake

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Comparative Analysis of Histone H3k4me3 Distribution in Mouse Liver in Different Diets Reveals the Epigenetic Efficacy of Cyanidin-3-O-Glucoside Dietary Intake International Journal of Molecular Sciences Article Comparative Analysis of Histone H3K4me3 Distribution in Mouse Liver in Different Diets Reveals the Epigenetic Efficacy of Cyanidin-3-O-glucoside Dietary Intake Giuseppe Persico 1,†, Francesca Casciaro 2,† , Alessandra Marinelli 3, Chiara Tonelli 3 , Katia Petroni 3,* and Marco Giorgio 1,2,* 1 Department of Experimental Oncology, IRCCS-European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy; [email protected] 2 Department of Biomedical Sciences, University of Padua, Via Ugo Bassi 58/B, 35131 Padova, Italy; [email protected] 3 Department of Biosciences, University of Milan, Via Celoria 26, 20133 Milan, Italy; [email protected] (A.M.); [email protected] (C.T.) * Correspondence: [email protected] (K.P.); [email protected] (M.G.) † These authors contributed equally to this work. Abstract: Background: Different diets result in significantly different phenotypes through metabolic and genomic reprogramming. Epigenetic marks, identified in humans and mouse models through caloric restriction, a high-fat diet or the intake of specific bioactives, suggest that genomic reprogram- ming drives this metabolic reprogramming and mediates the effect of nutrition on health. Histone modifications encode the epigenetic signal, which adapts genome functions to environmental con- Citation: Persico, G.; Casciaro, F.; ditions, including diets, by tuning the structure and properties of chromatin. To date, the effect of Marinelli, A.; Tonelli, C.; Petroni, K.; different diets on the genome-wide distribution of critical histone marks has not been determined. Giorgio, M. Comparative Analysis of Histone H3K4me3 Distribution in Methods: Using chromatin immunoprecipitation sequencing, we investigated the distribution of the Mouse Liver in Different Diets trimethylation of lysine 4 of histone H3 in the liver of mice fed for one year with five different diets, Reveals the Epigenetic Efficacy of including: chow containing yellow corn powder as an extra source of plant bioactives or specifically Cyanidin-3-O-glucoside Dietary enriched with Cyanidin-3-O-Glucoside, high-fat-enriched obesogenic diets, and caloric-restricted Intake. Int. J. Mol. Sci. 2021, 22, 6503. pro-longevity diets. Conclusions: Comparison of the resulting histone mark profiles revealed that https://doi.org/10.3390/ijms22126503 functional food containing cyanidin determines a broad effect. Academic Editor: Keywords: diets; functional food; anthocyanins; epigenetics; histone modifications; mouse liver Maurizio Margaglione Received: 22 May 2021 Accepted: 14 June 2021 1. Introduction Published: 17 June 2021 Diet is among the most effective environmental factors in inducing phenotypic Publisher’s Note: MDPI stays neutral changes. Caloric restriction (CR) and high-fat (HF) diets are significant examples: CR with regard to jurisdictional claims in increases longevity and retards aging in a variety of organisms [1], whereas a long-term, published maps and institutional affil- high-fat-enriched diet induces well-known pathological traits in mammals [2,3]. Epigenetic iations. mechanisms have been hypothesized to mediate the biological effects of diet, including regulation of the incidence of aging-associated diseases and life span [4,5]. Histone tail modifications are covalent reversible post-translational modifications that regulate chromatin structure and affect genome functions, particularly gene expression and DNA repair. Hundreds of histone modifications have been identified regulating Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. chromatin states and genome functions [6]. The trimethylation of lysine 4 of histone H3 This article is an open access article (H3K4me3) is an extensively investigated histone modification involved in the chromatin distributed under the terms and remodeling of processes associated with transcription and frequent on the promoters of conditions of the Creative Commons actively transcribed genes in the mouse [7] and humans [8]. Attribution (CC BY) license (https:// As observed for diets based on the restriction or variation in macronutrient composi- creativecommons.org/licenses/by/ tion, preclinical studies suggest that the dietary intake of polyphenols impacts the onset 4.0/). and progression of several diseases through epigenetic mechanisms, including targeting Int. J. Mol. Sci. 2021, 22, 6503. https://doi.org/10.3390/ijms22126503 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 10 As observed for diets based on the restriction or variation in macronutrient compo- sition, preclinical studies suggest that the dietary intake of polyphenols impacts the onset Int. J. Mol. Sci. 2021, and22, 6503 progression of several diseases through epigenetic mechanisms, including targeting 2 of 10 histone modifier enzymes [9]. Cyanidin-3-O-glucoside (C3G) is the most abundant among the anthocyanins, a class of plant flavonoids present in the human diet. C3G is abundant in fresh fruits,histone such as modifier grapes, enzymes berries, blood [9]. Cyanidin-3- oranges, peaches,O-Glucoside and (C3G) apples, is theand most derived abundant among beverages or pigmentedthe anthocyanins, cereals, asuch class as of rice plant and flavonoids corn with the present typical in thepurple human color diet. [10,11]. C3G is abundant Several preclinicalin fresh fruits, studies such have as grapes,establish berries,ed that bloodC3G dietary oranges, intake peaches, induces and healthy apples, and derived effects such as:beverages anti-obesity or pigmented and anti-infla cereals,mmatory such as [12–14], rice and anti-cancer corn with the[15], typical and cardio purple color [10,11]. [16] and neuroprotectiveSeveral [17,18]. preclinical At studiesthe biochemical have established level, C3G that and C3G its dietary metabolites intake are induces healthy shown to targeteffects a variety such as: ofanti-obesity regulatory andpathways anti-inflammatory within cells: [ 12AMPK-mTOR-S6K–14], anti-cancer [15 [19],], and cardio [16] Cox2 [20], NF-kBand [21], neuroprotective Caspases/PARP [17,18 [22],]. At Stat/Vegf the biochemical [23], and level,Sirtuin C3G 1 [24]. and In its laboratory metabolites are shown mice, the transcriptionto target a profiles variety of regulatoryskeletal muscle pathways [25], liver within [26], cells: fat AMPK-mTOR-S6K[27], retina [28], and [19 ], Cox2 [20], heart cells [29]NF-kB were [consistently21], Caspases/PARP found to be [22 largely], Stat/Vegf influenced [23], and by Sirtuinthe dietary 1 [24 intake]. In laboratory of mice, C3G. the transcription profiles of skeletal muscle [25], liver [26], fat [27], retina [28], and heart Despite thecells abundance [29] were consistentlyof biological foundeffects to attributed be largely to influenced polyphenols by and the dietarytheir simi- intake of C3G. larities with the effectDespite of caloric the abundance restriction of or biological high-fat effectsdiets, a attributed comparative to polyphenols study of the and their sim- effects of differentilarities diets with on thethe effectdistributi of caloricon of histone restriction marks or high-fatis not yet diets, available. a comparative study of the effects of different diets on the distribution of histone marks is not yet available. 2. Results 2. Results 2.1. Yellow and2.1. Purple Yellow Corn and Diet Purples Did Corn Not DietsAffect Did Body Not Weight Affect Body Weight Fifteen C57Bl/6JFifteen females, C57Bl/6J belonging females, to six belonging litters, were to six randomly litters, were divided randomly into five divided into five groups (n = 3groups mice/group) (n = 3 at mice/group) the age of three at the months, age of three and each months, group and was each fed group for ten was fed for ten months with themonths following with thefive following different fivediets: different (1) caloric diets: restriction (1) caloric (CR), restriction (2) high-fat-diet (CR), (2) high-fat-diet ad libitum (HF),ad libitum(3) purple (HF), corn-based (3) purple ad corn-based libitum (RD), ad libitum(4) yellow (RD), corn-based (4) yellow ad corn-based libitum ad libitum (YD), and (5) (YD),standard and diet (5) standardad libitum diet (SD). ad libitum (SD). More specifically,More we specifically, compared we a flavonoid-rich compared a flavonoid-rich diet, including diet, ACNs including from B1 ACNs Pl1 from B1 Pl1 purple corn (RD),purple with corn a flavonoid-rich (RD), with a flavonoid-rich ACN-free diet ACN-free from b1 pl1 diet yellow from b1corn pl1 (YD)yellow using corn (YD) using near-isogenic near-isogeniccorn lines, to determine corn lines, the to determine effect of dietary the effect ACNs of dietary on H3K4me3 ACNs onepigenetic H3K4me3 epigenetic marks. Previousmarks. HPLC Previous analysis HPLC of the analysis anthocyanin of the composition anthocyanin of composition B1 Pl1 seeds of showedB1 Pl1 seeds showed mostly cyanidinmostly 3-O-glucoside cyanidin 3- (C3G)O-glucoside and its (C3G)malonyl and derivatives, its malonyl whereas derivatives, b1 pl1 whereas seeds b1 pl1 seeds were devoid ofwere anthocyanins. devoid of anthocyanins. Apart from ACNs, Apart a from comparable ACNs, atotal comparable amount of total flavonoids amount of flavonoids is present in purpleis present and in yellow purple corn and [16]. yellow corn [16]. At the end of eachAt the dietary end of treatment, each dietary body treatment, weight in bodythe SD, weight YD, and in RD the groups SD, YD, was and RD groups significantly greaterwas significantly than that in greater the CR than
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