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Epigenetics in Metabolic and Neurological Disorders
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Epigenetics in Metabolic and Neurological Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (22 December 2019) | Viewed by 47625

Special Issue Editor

Prof. Dr. Liborio Stuppia

E-Mail Website
Guest Editor
School of Medicine and Health Sciences, G. d’Annunzio University, Chieti, Italy
Interests: medical genetics; genetics and epigenetics of human reproduction; stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epigenetics is a gene regulation mechanism based on chemical modifications of genomic DNA and histone proteins, as well as to the production of miRNA. Epigenetic alterations can cause congenital disorders, including genomic imprinting disorders, X-chromosome inactivation disorders and epigenetic regulation-associated molecule disorders. However, it has been recently suggested that epigenetic mechanisms could be also related to an increased susceptibility to metabolic and neurological disorders throughout lifetime.  

Epigenetic modifications in DNA are vulnerable to environmental stress, such as malnutrition, environmental chemicals and mental stress, mostly occurring during the early period of life, but also during prenatal life and even during maternal and paternal gametogenesis.

Since the epigenome has a reversible property, induced epigenomic alterations can be potentially restored, leading to the possibility of an epigenomic-based preemptive medicine consisting of early detection of epigenomic signatures and early intervention.

In this Special Issue, I would like to invite review and original articles that focus on the epigenetic basis of the susceptibility of metabolic and neurological diseases in the frame of preventive strategies involving early life, prenatal life and periconceptional life. 

Prof. Dr. Liborio Stuppia
Guest Editor

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Related Special Issues

Published Papers (9 papers)

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Research

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10 pages, 899 KiB  
Article
Association of Obesity with DNA Methylation Age Acceleration in African American Mothers from the InterGEN Study
by Chengchen Li, Zeyuan Wang, Theresa Hardy, Yunfeng Huang, Qin Hui, Cindy A. Crusto, Michelle L. Wright, Jacquelyn Y. Taylor and Yan V. Sun
Int. J. Mol. Sci. 2019, 20(17), 4273; https://doi.org/10.3390/ijms20174273 - 31 Aug 2019
Cited by 29 | Viewed by 4822
Abstract
African American women are affected by earlier onset of age-associated health deteriorations and obesity disproportionally, but little is known about the mechanism linking body mass index (BMI) and biological aging among this population. DNA methylation age acceleration (DNAm AA), measuring the difference between [...] Read more.
African American women are affected by earlier onset of age-associated health deteriorations and obesity disproportionally, but little is known about the mechanism linking body mass index (BMI) and biological aging among this population. DNA methylation age acceleration (DNAm AA), measuring the difference between DNA methylation age and chronological age, is a novel biomarker of the biological aging process, and predicts aging-related disease outcomes. The present study estimated cross-tissue DNA methylation age acceleration using saliva samples from 232 African American mothers. Cross-sectional regression analyses were performed to assess the association of BMI with DNAm AA. The average chronological age and DNA methylation age were 31.67 years, and 28.79 years, respectively. After adjusting for smoking, hypertension diagnosis history, and socioeconomic factors (education, marital status, household income), a 1 kg/m2 increase in BMI is associated with 0.14 years increment of DNAm AA (95% CI: (0.08, 0.21)). The conclusion: in African American women, high BMI is independently associated with saliva-based DNA methylation age acceleration, after adjusting for smoking, hypertension, and socioeconomic status. This finding supports that high BMI accelerates biological aging, and plays a key role in age-related disease outcomes among African American women. Full article
(This article belongs to the Special Issue Epigenetics in Metabolic and Neurological Disorders)
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11 pages, 1171 KiB  
Communication
Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels
by Fabio Coppedè, Andrea Stoccoro, Pierpaola Tannorella, Roberta Gallo, Vanessa Nicolì and Lucia Migliore
Int. J. Mol. Sci. 2019, 20(15), 3754; https://doi.org/10.3390/ijms20153754 - 31 Jul 2019
Cited by 35 | Viewed by 5127
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in the one-carbon metabolism, a metabolic pathway required for DNA synthesis and methylation reactions. MTHFR hypermethylation, resulting in reduced gene expression, can contribute to several human disorders, but little is still known about the factors that [...] Read more.
Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in the one-carbon metabolism, a metabolic pathway required for DNA synthesis and methylation reactions. MTHFR hypermethylation, resulting in reduced gene expression, can contribute to several human disorders, but little is still known about the factors that regulate MTHFR methylation levels. We performed the present study to investigate if common polymorphisms in one-carbon metabolism genes contribute to MTHFR methylation levels. MTHFR methylation was assessed in peripheral blood DNA samples from 206 healthy subjects with methylation-sensitive high-resolution melting (MS-HRM); genotyping was performed for MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), MTRR 66A>G (rs1801394), MTR 2756A>G (rs1805087), SLC19A1 (RFC1) 80G>A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp ins/del (rs34489327), DNMT3A -448A>G (rs1550117), and DNMT3B -149C>T (rs2424913) polymorphisms. We observed a statistically significant effect of the DNMT3B -149C>T polymorphism on mean MTHFR methylation levels, and particularly CT and TT carriers showed increased methylation levels than CC carriers. The present study revealed an association between a functional polymorphism of DNMT3B and MTHFR methylation levels that could be of relevance in those disorders, such as inborn defects, metabolic disorders and cancer, that have been linked to impaired DNA methylation. Full article
(This article belongs to the Special Issue Epigenetics in Metabolic and Neurological Disorders)
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14 pages, 5384 KiB  
Article
Metabolic and Immunological Shifts during Mid-to-Late Gestation Influence Maternal Blood Methylation of CPT1A and SREBF1
by Shilpa Pavethynath, Chihiro Imai, Xin Jin, Naomi Hichiwa, Hidemi Takimoto, Motoko Okamitsu, Iori Tarui, Tomoko Aoyama, Satoshi Yago, Ayako Fudono, Masaaki Muramatsu, Naoyuki Miyasaka and Noriko Sato
Int. J. Mol. Sci. 2019, 20(5), 1066; https://doi.org/10.3390/ijms20051066 - 1 Mar 2019
Cited by 10 | Viewed by 3732
Abstract
Mid-to-late gestation is a unique period in which women experience dynamic changes in lipid metabolism. Although the recent intensive epigenome-wide association studies (EWAS) using peripheral leukocytes have revealed that lipid-related traits alter DNA methylation, the influence of pregnancy-induced metabolic changes on the methylation [...] Read more.
Mid-to-late gestation is a unique period in which women experience dynamic changes in lipid metabolism. Although the recent intensive epigenome-wide association studies (EWAS) using peripheral leukocytes have revealed that lipid-related traits alter DNA methylation, the influence of pregnancy-induced metabolic changes on the methylation levels of these differentially methylated sites is not well known. In this study, we performed a prospective cohort study of pregnant women (n = 52) using the MassARRAY EpiTYPER assay and analyzed the methylation levels of variably methylated sites, including CPT1A intron 1 and SREBF1 intron 1 CpGs, which were previously verified to be robustly associated with adiposity traits. Although methylation of SREBF1 was associated with body mass index (BMI) and low-density lipoprotein cholesterol at mid-gestation, this association was attenuated at late gestation, which was consistent with the metabolic switch from an anabolic to a catabolic state. However, the BMI association with CPT1A intron 1 methylation appeared to strengthen at late gestation; this association was mediated by pre-pregnancy BMI-dependent change in the leukocyte proportion during mid-to-late gestation. Thus, the methylation of adiposity-related differentially methylated regions was sensitive to metabolic and immunological changes during mid-to-late gestation. Full article
(This article belongs to the Special Issue Epigenetics in Metabolic and Neurological Disorders)
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16 pages, 2299 KiB  
Article
Histone H3 Lysine 9 Acetylation is Downregulated in GDM Placentas and Calcitriol Supplementation Enhanced This Effect
by Paula Hepp, Stefan Hutter, Julia Knabl, Simone Hofmann, Christina Kuhn, Sven Mahner and Udo Jeschke
Int. J. Mol. Sci. 2018, 19(12), 4061; https://doi.org/10.3390/ijms19124061 - 14 Dec 2018
Cited by 19 | Viewed by 4703
Abstract
Despite the ever-rising incidence of Gestational Diabetes Mellitus (GDM) and its implications for long-term health of mothers and offspring, the underlying molecular mechanisms remain to be elucidated. To contribute to this, the present study’s objectives are to conduct a sex-specific analysis of active [...] Read more.
Despite the ever-rising incidence of Gestational Diabetes Mellitus (GDM) and its implications for long-term health of mothers and offspring, the underlying molecular mechanisms remain to be elucidated. To contribute to this, the present study’s objectives are to conduct a sex-specific analysis of active histone modifications in placentas affected by GDM and to investigate the effect of calcitriol on trophoblast cell’s transcriptional status. The expression of Histone H3 lysine 9 acetylation (H3K9ac) and Histone H3 lysine 4 trimethylation (H3K4me3) was evaluated in 40 control and 40 GDM (20 male and 20 female each) placentas using immunohistochemistry and immunofluorescence. The choriocarcinoma cell line BeWo and primary human villous trophoblast cells were treated with calcitriol (48 h). Thereafter, western blots were used to quantify concentrations of H3K9ac and the transcription factor FOXO1. H3K9ac expression was downregulated in GDM placentas, while H3K4me3 expression was not significantly different. Cell culture experiments showed a slight downregulation of H3K9ac after calcitriol stimulation at the highest concentration. FOXO1 expression showed a dose-dependent increase. Our data supports previous research suggesting that epigenetic dysregulations play a key role in gestational diabetes mellitus. Insufficient transcriptional activity may be part of its pathophysiology and this cannot be rescued by calcitriol. Full article
(This article belongs to the Special Issue Epigenetics in Metabolic and Neurological Disorders)
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Review

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16 pages, 249 KiB  
Review
Epigenetics and Neurological Disorders in ART
by Marina La Rovere, Marica Franzago and Liborio Stuppia
Int. J. Mol. Sci. 2019, 20(17), 4169; https://doi.org/10.3390/ijms20174169 - 26 Aug 2019
Cited by 23 | Viewed by 4294
Abstract
About 1–4% of children are currently generated by Assisted Reproductive Technologies (ART) in developed countries. These babies show only a slightly increased risk of neonatal malformations. However, follow-up studies have suggested a higher susceptibility to multifactorial, adult onset disorders like obesity, diabetes and [...] Read more.
About 1–4% of children are currently generated by Assisted Reproductive Technologies (ART) in developed countries. These babies show only a slightly increased risk of neonatal malformations. However, follow-up studies have suggested a higher susceptibility to multifactorial, adult onset disorders like obesity, diabetes and cardiovascular diseases in ART offspring. It has been suggested that these conditions could be the consequence of epigenetic, alterations, due to artificial manipulations of gametes and embryos potentially able to alter epigenetic stability during zygote reprogramming. In the last years, epigenetic alterations have been invoked as a possible cause of increased risk of neurological disorders, but at present the link between epigenetic modifications and long-term effects in terms of neurological diseases in ART children remains unclear, due to the short follow up limiting retrospective studies. In this review, we summarize the current knowledge about neurological disorders promoted by epigenetics alterations in ART. Based on data currently available, it is possible to conclude that little, if any, evidence of an increased risk of neurological disorders in ART conceived children is provided. Most important, the large majority of reports appears to be limited to epidemiological studies, not providing any experimental evidence about epigenetic modifications responsible for an increased risk. Full article
(This article belongs to the Special Issue Epigenetics in Metabolic and Neurological Disorders)
20 pages, 1738 KiB  
Review
Epigenetic Regulation of Adipogenic Differentiation by Histone Lysine Demethylation
by Geovanny I. Nic-Can, Beatriz A. Rodas-Junco, Leydi M. Carrillo-Cocom, Alejandro Zepeda-Pedreguera, Ricardo Peñaloza-Cuevas, Fernando J. Aguilar-Ayala and Rafael A. Rojas-Herrera
Int. J. Mol. Sci. 2019, 20(16), 3918; https://doi.org/10.3390/ijms20163918 - 12 Aug 2019
Cited by 26 | Viewed by 5375
Abstract
Obesity is a rising public health problem that contributes to the development of several metabolic diseases and cancer. Adipocyte precursors outside of adipose depots that expand due to overweight and obesity may have a negative impact on human health. Determining how progenitor cells [...] Read more.
Obesity is a rising public health problem that contributes to the development of several metabolic diseases and cancer. Adipocyte precursors outside of adipose depots that expand due to overweight and obesity may have a negative impact on human health. Determining how progenitor cells acquire a preadipocyte commitment and become mature adipocytes remains a significant challenge. Over the past several years, we have learned that the establishment of cellular identity is widely influenced by changes in histone marks, which in turn modulate chromatin structure. In this regard, histone lysine demethylases (KDMs) are now emerging as key players that shape chromatin through their ability to demethylate almost all major histone methylation sites. Recent research has shown that KDMs orchestrate the chromatin landscape, which mediates the activation of adipocyte-specific genes. In addition, KDMs have functions in addition to their enzymatic activity, which are beginning to be revealed, and their dysregulation seems to be related to the development of metabolic disorders. In this review, we highlight the biological functions of KDMs that contribute to the establishment of a permissive or repressive chromatin environment during the mesenchymal stem cell transition into adipocytes. Understanding how KDMs regulate adipogenesis might prompt the development of new strategies for fighting obesity-related diseases. Full article
(This article belongs to the Special Issue Epigenetics in Metabolic and Neurological Disorders)
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17 pages, 1830 KiB  
Review
Global DNA Methylation Patterns in Human Gliomas and Their Interplay with Other Epigenetic Modifications
by Michal J. Dabrowski and Bartosz Wojtas
Int. J. Mol. Sci. 2019, 20(14), 3478; https://doi.org/10.3390/ijms20143478 - 15 Jul 2019
Cited by 34 | Viewed by 5856
Abstract
During the last two decades, several international consortia have been established to unveil the molecular background of human cancers including gliomas. As a result, a huge outbreak of new genetic and epigenetic data appeared. It was not only shown that gliomas share some [...] Read more.
During the last two decades, several international consortia have been established to unveil the molecular background of human cancers including gliomas. As a result, a huge outbreak of new genetic and epigenetic data appeared. It was not only shown that gliomas share some specific DNA sequence aberrations, but they also present common alterations of chromatin. Many researchers have reported specific epigenetic features, such as DNA methylation and histone modifications being involved in tumor pathobiology. Unlike mutations in DNA, epigenetic changes are more global in nature. Moreover, many studies have shown an interplay between different types of epigenetic changes. Alterations in DNA methylation in gliomas are one of the best described epigenetic changes underlying human pathology. In the following work, we present the state of knowledge about global DNA methylation patterns in gliomas and their interplay with histone modifications that may affect transcription factor binding, global gene expression and chromatin conformation. Apart from summarizing the impact of global DNA methylation on glioma pathobiology, we provide an extract of key mechanisms of DNA methylation machinery. Full article
(This article belongs to the Special Issue Epigenetics in Metabolic and Neurological Disorders)
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26 pages, 1258 KiB  
Review
Can Epigenetics of Endothelial Dysfunction Represent the Key to Precision Medicine in Type 2 Diabetes Mellitus?
by Celeste Coco, Luca Sgarra, Maria Assunta Potenza, Carmela Nacci, Barbara Pasculli, Raffaela Barbano, Paola Parrella and Monica Montagnani
Int. J. Mol. Sci. 2019, 20(12), 2949; https://doi.org/10.3390/ijms20122949 - 17 Jun 2019
Cited by 27 | Viewed by 6757
Abstract
In both developing and industrialized Countries, the growing prevalence of Type 2 Diabetes Mellitus (T2DM) and the severity of its related complications make T2DM one of the most challenging metabolic diseases worldwide. The close relationship between genetic and environmental factors suggests that eating [...] Read more.
In both developing and industrialized Countries, the growing prevalence of Type 2 Diabetes Mellitus (T2DM) and the severity of its related complications make T2DM one of the most challenging metabolic diseases worldwide. The close relationship between genetic and environmental factors suggests that eating habits and unhealthy lifestyles may significantly affect metabolic pathways, resulting in dynamic modifications of chromatin-associated proteins and homeostatic transcriptional responses involved in the progression of T2DM. Epigenetic mechanisms may be implicated in the complex processes linking environmental factors to genetic predisposition to metabolic disturbances, leading to obesity and type 2 diabetes mellitus (T2DM). Endothelial dysfunction represents an earlier marker and an important player in the development of this disease. Dysregulation of the endothelial ability to produce and release vasoactive mediators is recognized as the initial feature of impaired vascular activity under obesity and other insulin resistance conditions and undoubtedly concurs to the accelerated progression of atherosclerotic lesions and overall cardiovascular risk in T2DM patients. This review aims to summarize the most current knowledge regarding the involvement of epigenetic changes associated with endothelial dysfunction in T2DM, in order to identify potential targets that might contribute to pursuing “precision medicine” in the context of diabetic illness. Full article
(This article belongs to the Special Issue Epigenetics in Metabolic and Neurological Disorders)
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13 pages, 704 KiB  
Review
Epigenetic Methylations on N6-Adenine and N6-Adenosine with the same Input but Different Output
by Zhiqing Li, Ping Zhao and Qingyou Xia
Int. J. Mol. Sci. 2019, 20(12), 2931; https://doi.org/10.3390/ijms20122931 - 15 Jun 2019
Cited by 21 | Viewed by 6445
Abstract
Epigenetic modifications on individual bases in DNA and RNA can encode inheritable genetic information beyond the canonical bases. Among the nucleic acid modifications, DNA N6-methadenine (6mA) and RNA N6-methyladenosine (m6A) have recently been well-studied due to the technological development of detection strategies and [...] Read more.
Epigenetic modifications on individual bases in DNA and RNA can encode inheritable genetic information beyond the canonical bases. Among the nucleic acid modifications, DNA N6-methadenine (6mA) and RNA N6-methyladenosine (m6A) have recently been well-studied due to the technological development of detection strategies and the functional identification of modification enzymes. The current findings demonstrate a wide spectrum of 6mA and m6A distributions from prokaryotes to eukaryotes and critical roles in multiple cellular processes. It is interesting that the processes of modification in which the methyl group is added to adenine and adenosine are the same, but the outcomes of these modifications in terms of their physiological impacts in organisms are quite different. In this review, we summarize the latest progress in the study of enzymes involved in the 6mA and m6A methylation machinery, including methyltransferases and demethylases, and their functions in various biological pathways. In particular, we focus on the mechanisms by which 6mA and m6A regulate the expression of target genes, and we highlight the future challenges in epigenetic regulation. Full article
(This article belongs to the Special Issue Epigenetics in Metabolic and Neurological Disorders)
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