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Journal ArticleDOI

Epigenetics of metabolic syndrome

01 Nov 2018-Physiological Genomics (American Physiological Society Bethesda, MD)-Vol. 50, Iss: 11, pp 947-955
TL;DR: In this article, a review summarizes recent breakthroughs regarding epigenetic markers in studies of obesity, Type II diabetes, and cardiovascular disease, the three major disorders associated with metabolic syndrome, and discuss open questions and future directions for integrating genomic, epigenomic, and phenotypic big biodata toward understanding metabolic syndrome etiology.
Abstract: The dramatic increase in global prevalence of metabolic disease is inexplicable when considering only environmental or only genetic factors, leading to the need to explore the possible roles of epigenetic factors. A great deal of progress has been made in this interdisciplinary field in recent years, with many studies investigating various aspects of the metabolic syndrome and its associated epigenetic changes. Rodent models of metabolic diseases have been particularly illuminating because of the ability to leverage tools such as genetic and environmental modifications. The current review summarizes recent breakthroughs regarding epigenetic markers in studies of obesity, Type II diabetes, and cardiovascular disease, the three major disorders associated with metabolic syndrome. We also discuss open questions and future directions for integrating genomic, epigenomic, and phenotypic big biodata toward understanding metabolic syndrome etiology.
Citations
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Feng Yue1, Feng Yue2, Yong Cheng3, Alessandra Breschi, Jeff Vierstra4, Weisheng Wu5, Weisheng Wu1, Tyrone Ryba6, Tyrone Ryba7, Richard Sandstrom4, Zhihai Ma3, Carrie A. Davis8, Benjamin D. Pope7, Yin Shen2, Dmitri D. Pervouchine, Sarah Djebali, Robert E. Thurman4, Rajinder Kaul4, Eric Rynes4, Anthony Kirilusha9, Georgi K. Marinov9, Brian A. Williams9, Diane Trout9, Henry Amrhein9, Katherine I. Fisher-Aylor9, Igor Antoshechkin9, Gilberto DeSalvo9, Lei Hoon See8, Meagan Fastuca8, Jorg Drenkow8, Chris Zaleski8, Alexander Dobin8, Pablo Prieto, Julien Lagarde, Giovanni Bussotti, Andrea Tanzer10, Olgert Denas11, Kanwei Li11, M. A. Bender4, M. A. Bender12, Miaohua Zhang12, Rachel Byron12, Mark Groudine12, Mark Groudine4, David McCleary2, Long Pham2, Zhen Ye2, Samantha Kuan2, Lee Edsall2, Yi-Chieh Wu13, Matthew D. Rasmussen13, Mukul S. Bansal13, Manolis Kellis14, Manolis Kellis13, Cheryl A. Keller1, Christapher S. Morrissey1, Tejaswini Mishra1, Deepti Jain1, Nergiz Dogan1, Robert S. Harris1, Philip Cayting3, Trupti Kawli3, Alan P. Boyle5, Alan P. Boyle3, Ghia Euskirchen3, Anshul Kundaje3, Shin Lin3, Yiing Lin3, Camden Jansen15, Venkat S. Malladi3, Melissa S. Cline16, Drew T. Erickson3, Vanessa M. Kirkup16, Katrina Learned16, Cricket A. Sloan3, Kate R. Rosenbloom16, Beatriz Lacerda de Sousa17, Kathryn Beal, Miguel Pignatelli, Paul Flicek, Jin Lian18, Tamer Kahveci19, Dongwon Lee20, W. James Kent16, Miguel Santos17, Javier Herrero21, Cedric Notredame, Audra K. Johnson4, Shinny Vong4, Kristen Lee4, Daniel Bates4, Fidencio Neri4, Morgan Diegel4, Theresa K. Canfield4, Peter J. Sabo4, Matthew S. Wilken4, Thomas A. Reh4, Erika Giste4, Anthony Shafer4, Tanya Kutyavin4, Eric Haugen4, Douglas Dunn4, Alex Reynolds4, Shane Neph4, Richard Humbert4, R. Scott Hansen4, Marella F. T. R. de Bruijn22, Licia Selleri23, Alexander Y. Rudensky24, Steven Z. Josefowicz24, Robert M. Samstein24, Evan E. Eichler4, Stuart H. Orkin25, Dana N. Levasseur26, Thalia Papayannopoulou4, Kai Hsin Chang4, Arthur I. Skoultchi27, Srikanta Gosh27, Christine M. Disteche4, Piper M. Treuting4, Yanli Wang1, Mitchell J. Weiss, Gerd A. Blobel28, Xiaoyi Cao2, Sheng Zhong2, Ting Wang29, Peter J. Good30, Rebecca F. Lowdon29, Rebecca F. Lowdon30, Leslie B. Adams30, Leslie B. Adams31, Xiao Qiao Zhou30, Michael J. Pazin30, Elise A. Feingold30, Barbara J. Wold9, James Taylor11, Ali Mortazavi15, Sherman M. Weissman18, John A. Stamatoyannopoulos4, Michael Snyder3, Roderic Guigó, Thomas R. Gingeras8, David M. Gilbert7, Ross C. Hardison1, Michael A. Beer20, Bing Ren2 
01 Nov 2014
TL;DR: By comparing with the human genome, this work not only confirms substantial conservation in the newly annotated potential functional sequences, but also finds a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization.
Abstract: The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.

226 citations

Journal ArticleDOI
TL;DR: The evidence suggests that leptin is both a target and a mediator of epigenetic changes that develop in numerous tissues during metabolic disorders.
Abstract: Nowadays, it is well-known that the deregulation of epigenetic machinery is a common biological event leading to the development and progression of metabolic disorders. Moreover, the expression level and actions of leptin, a vast adipocytokine regulating energy metabolism, appear to be strongly associated with epigenetics. Therefore, the aim of this review was to summarize the current knowledge of the epigenetic regulation of leptin as well as the leptin-induced epigenetic modifications in metabolic disorders and associated phenomena. The collected data indicated that the deregulation of leptin expression and secretion that occurs during the course of metabolic diseases is underlain by a variation in the level of promoter methylation, the occurrence of histone modifications, along with miRNA interference. Furthermore, leptin was proven to epigenetically regulate several miRNAs and affect the activity of the histone deacetylases. These epigenetic modifications were observed in obesity, gestational diabetes, metabolic syndrome and concerned various molecular processes like glucose metabolism, insulin sensitivity, liver fibrosis, obesity-related carcinogenesis, adipogenesis or fetal/early postnatal programming. Moreover, the circulating miRNA profiles were associated with the plasma leptin level in metabolic syndrome, and miRNAs were found to be involved in hypothalamic leptin sensitivity. In summary, the evidence suggests that leptin is both a target and a mediator of epigenetic changes that develop in numerous tissues during metabolic disorders.

26 citations

Journal ArticleDOI
TL;DR: An overview of the most important epigenetic pathways is required to identify potential molecular targets to treat or prevent obesity-related endothelial dysfunction and atherosclerotic disease and to enable the employment of precision medicine approaches in this setting.
Abstract: Significance: The prevalence of obesity and cardiometabolic phenotypes is alarmingly increasing across the globe and is associated with atherosclerotic vascular complications and high mortality. In spite of multifactorial interventions, vascular residual risk remains high in this patient population, suggesting the need for breakthrough therapies. The mechanisms underpinning obesity-related vascular disease remain elusive and represent an intense area of investigation. Recent Advances: Epigenetic modifications-defined as environmentally induced chemical changes of DNA and histones that do not affect DNA sequence-are emerging as a potent modulator of gene transcription in the vasculature and might significantly contribute to the development of obesity-induced endothelial dysfunction. DNA methylation and histone post-translational modifications cooperate to build complex epigenetic signals, altering transcriptional networks that are implicated in redox homeostasis, mitochondrial function, vascular inflammation, and perivascular fat homeostasis in patients with cardiometabolic disturbances. Critical Issues: Deciphering the epigenetic landscape in the vasculature is extremely challenging due to the complexity of epigenetic signals and their function in regulating transcription. An overview of the most important epigenetic pathways is required to identify potential molecular targets to treat or prevent obesity-related endothelial dysfunction and atherosclerotic disease. This would enable the employment of precision medicine approaches in this setting. Future Directions: Current and future research efforts in this field entail a better definition of the vascular epigenome in obese patients as well as the unveiling of novel, cell-specific chromatin-modifying drugs that are able to erase specific epigenetic signals that are responsible for maladaptive transcriptional alterations and vascular dysfunction in obese patients. Antioxid. Redox Signal. 34, 1165-1199.

19 citations

Journal ArticleDOI
TL;DR: In this article, the authors looked at biochemical mechanisms and epigenetic modifications associated with HIV, ARVs, and MetS, focusing on mitochondrial dysfunction, insulin resistance, inflammation, lipodystrophy, and dyslipidaemia.
Abstract: Metabolic syndrome (MetS) is a non-communicable disease characterised by a cluster of metabolic irregularities. Alarmingly, the prevalence of MetS in people living with Human Immunodeficiency Virus (HIV) and antiretroviral (ARV) usage is increasing rapidly. This study aimed to look at biochemical mechanisms and epigenetic modifications associated with HIV, ARVs, and MetS. More specifically, emphasis was placed on mitochondrial dysfunction, insulin resistance, inflammation, lipodystrophy, and dyslipidaemia. We found that mitochondrial dysfunction was the most common mechanism that induced metabolic complications. Our findings suggest that protease inhibitors (PIs) are more commonly implicated in MetS-related effects than other classes of ARVs. Furthermore, we highlight epigenetic studies linking HIV and ARV usage to MetS and stress the need for more studies, as the current literature remains limited despite the advancement in and popularity of epigenetics.

15 citations

Journal ArticleDOI
TL;DR: How nutritional status either leads to an increase of MEG3 expression that protects against cancer and metabolic dysfunctions, or to its downregulation minimizing its pleiotropic costs of expression is discussed.

9 citations

References
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Journal ArticleDOI
06 Sep 2012-Nature
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

13,548 citations

Journal ArticleDOI
TL;DR: It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool, and a single set of cut points would be used for all components except waist circumference, for which further work is required.
Abstract: A cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone, have become known as the metabolic syndrome. The risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. Most recently, these have come from the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute. The main difference concerns the measure for central obesity, with this being an obligatory component in the International Diabetes Federation definition, lower than in the American Heart Association/National Heart, Lung, and Blood Institute criteria, and ethnic specific. The present article represents the outcome of a meeting between several major organizations in an attempt to unify criteria. It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool. Three abnormal findings out of 5 would qualify a person for the metabolic syndrome. A single set of cut points would be used for all components except waist circumference, for which further work is required. In the interim, national or regional cut points for waist circumference can be used.

11,737 citations

Journal ArticleDOI
16 Jan 2002-JAMA
TL;DR: These results from a representative sample of US adults show that the metabolic syndrome is highly prevalent and the large numbers of US residents with the metabolic Syndrome may have important implications for the health care sector.
Abstract: ContextThe Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) highlights the importance of treating patients with the metabolic syndrome to prevent cardiovascular disease. Limited information is available about the prevalence of the metabolic syndrome in the United States, however.ObjectiveTo estimate the prevalence of the metabolic syndrome in the United States as defined by the ATP III report.Design, Setting, and ParticipantsAnalysis of data on 8814 men and women aged 20 years or older from the Third National Health and Nutrition Examination Survey (1988-1994), a cross-sectional health survey of a nationally representative sample of the noninstitutionalized civilian US population.Main Outcome MeasuresPrevalence of the metabolic syndrome as defined by ATP III (≥3 of the following abnormalities): waist circumference greater than 102 cm in men and 88 cm in women; serum triglycerides level of at least 150 mg/dL (1.69 mmol/L); high-density lipoprotein cholesterol level of less than 40 mg/dL (1.04 mmol/L) in men and 50 mg/dL (1.29 mmol/L) in women; blood pressure of at least 130/85 mm Hg; or serum glucose level of at least 110 mg/dL (6.1 mmol/L).ResultsThe unadjusted and age-adjusted prevalences of the metabolic syndrome were 21.8% and 23.7%, respectively. The prevalence increased from 6.7% among participants aged 20 through 29 years to 43.5% and 42.0% for participants aged 60 through 69 years and aged at least 70 years, respectively. Mexican Americans had the highest age-adjusted prevalence of the metabolic syndrome (31.9%). The age-adjusted prevalence was similar for men (24.0%) and women (23.4%). However, among African Americans, women had about a 57% higher prevalence than men did and among Mexican Americans, women had about a 26% higher prevalence than men did. Using 2000 census data, about 47 million US residents have the metabolic syndrome.ConclusionsThese results from a representative sample of US adults show that the metabolic syndrome is highly prevalent. The large numbers of US residents with the metabolic syndrome may have important implications for the health care sector.

6,961 citations

Journal ArticleDOI
15 May 2009-Science
TL;DR: It is shown here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro.
Abstract: DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference–mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.

5,155 citations

Journal ArticleDOI
15 Apr 2010-Nature
TL;DR: It is shown that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression, indicating that l incRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
Abstract: Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.

4,605 citations

Trending Questions (2)
What are the epigenetic changes that occur in metabolic syndrome?

The paper discusses recent breakthroughs in epigenetic markers in studies of obesity, Type II diabetes, and cardiovascular disease, which are the three major disorders associated with metabolic syndrome. However, it does not specifically mention the epigenetic changes that occur in metabolic syndrome.

How does epigenetic affects metabolic syndrome?

Epigenetic factors play a role in the development of metabolic syndrome, as evidenced by studies investigating epigenetic changes in obesity, Type II diabetes, and cardiovascular disease.