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13 pages, 1922 KiB

Open AccessArticle

Ultra-Deep DNA Methylation Analysis of X-Linked Genes: GLA and AR as Model Genes

by Giulia De Riso, Mariella Cuomo, Teodolinda Di Risi, Rosa Della Monica, Michela Buonaiuto, Davide Costabile, Antonio Pisani, Sergio Cocozza and Lorenzo Chiariotti

Genes 2020, 11(6), 620; https://doi.org/10.3390/genes11060620 - 04 Jun 2020

Cited by 7 | Viewed by 3351

Abstract

Recessive X-linked disorders may occasionally evolve in clinical manifestations of variable severity also in female carriers. For some of such diseases, the frequency of the symptoms’ appearance during women’s life may be particularly relevant. This phenomenon has been largely attributed to the potential [...] Read more.

Recessive X-linked disorders may occasionally evolve in clinical manifestations of variable severity also in female carriers. For some of such diseases, the frequency of the symptoms’ appearance during women’s life may be particularly relevant. This phenomenon has been largely attributed to the potential skewness of the X-inactivation process leading to variable phenotypes. Nonetheless, in many cases, no correlation with X-inactivation unbalance was demonstrated. However, methods for analyzing skewness have been mainly limited to Human Androgen Receptor methylation analysis (HUMARA). Recently, the X-inactivation process has been largely revisited, highlighting the heterogeneity existing among loci in the epigenetic state within inactive and, possibly, active X-chromosomes. We reasoned that gene-specific and ultra-deep DNA methylation analyses could greatly help to unravel details of the X-inactivation process and the roles of specific X genes inactivation in disease manifestations. We recently provided evidence that studying DNA methylation at specific autosomic loci at a single-molecule resolution (epiallele distribution analysis) allows one to analyze cell-to-cell methylation differences in a given cell population. We here apply the epiallele analysis at two X-linked loci to investigate whether females show allele-specific epiallelic patterns. Due to the high potential of this approach, the method allows us to obtain clearly distinct allele-specific epiallele profiles. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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20 pages, 4373 KiB

Open AccessArticle

DNA Methylation Module Network-Based Prognosis and Molecular Typing of Cancer

by Ze-Jia Cui, Xiong-Hui Zhou and Hong-Yu Zhang

Genes 2019, 10(8), 571; https://doi.org/10.3390/genes10080571 - 28 Jul 2019

Cited by 13 | Viewed by 3698

Abstract

Achieving cancer prognosis and molecular typing is critical for cancer treatment. Previous studies have identified some gene signatures for the prognosis and typing of cancer based on gene expression data. Some studies have shown that DNA methylation is associated with cancer development, progression, [...] Read more.

Achieving cancer prognosis and molecular typing is critical for cancer treatment. Previous studies have identified some gene signatures for the prognosis and typing of cancer based on gene expression data. Some studies have shown that DNA methylation is associated with cancer development, progression, and metastasis. In addition, DNA methylation data are more stable than gene expression data in cancer prognosis. Therefore, in this work, we focused on DNA methylation data. Some prior researches have shown that gene modules are more reliable in cancer prognosis than are gene signatures and that gene modules are not isolated. However, few studies have considered cross-talk among the gene modules, which may allow some important gene modules for cancer to be overlooked. Therefore, we constructed a gene co-methylation network based on the DNA methylation data of cancer patients, and detected the gene modules in the co-methylation network. Then, by permutation testing, cross-talk between every two modules was identified; thus, the module network was generated. Next, the core gene modules in the module network of cancer were identified using the K-shell method, and these core gene modules were used as features to study the prognosis and molecular typing of cancer. Our method was applied in three types of cancer (breast invasive carcinoma, skin cutaneous melanoma, and uterine corpus endometrial carcinoma). Based on the core gene modules identified by the constructed DNA methylation module networks, we can distinguish not only the prognosis of cancer patients but also use them for molecular typing of cancer. These results indicated that our method has important application value for the diagnosis of cancer and may reveal potential carcinogenic mechanisms. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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15 pages, 2539 KiB

Open AccessArticle

Methylome-Wide Association Study in Peripheral White Blood Cells Focusing on Central Obesity and Inflammation

by Ana Arpón, Fermín I. Milagro, Omar Ramos-Lopez, Maria L. Mansego, José-Ignacio Riezu-Boj and J. Alfredo Martínez

Genes 2019, 10(6), 444; https://doi.org/10.3390/genes10060444 - 11 Jun 2019

Cited by 14 | Viewed by 3462

Abstract

Epigenetic signatures such as DNA methylation may be associated with specific obesity traits in different tissues. The onset and development of some obesity-related complications are often linked to visceral fat accumulation. The aim of this study was to explore DNA methylation levels in [...] Read more.

Epigenetic signatures such as DNA methylation may be associated with specific obesity traits in different tissues. The onset and development of some obesity-related complications are often linked to visceral fat accumulation. The aim of this study was to explore DNA methylation levels in peripheral white blood cells to identify epigenetic methylation marks associated with waist circumference (WC). DNA methylation levels were assessed using Infinium Human Methylation 450K and MethylationEPIC beadchip (Illumina) to search for putative associations with WC values of 473 participants from the Methyl Epigenome Network Association (MENA) project. Statistical analysis and Ingenuity Pathway Analysis (IPA) were employed for assessing the relationship between methylation and WC. A total of 669 CpGs were statistically associated with WC (FDR < 0.05, slope ≥ |0.1|). From these CpGs, 375 CpGs evidenced a differential methylation pattern between females with WC ≤ 88 and > 88 cm, and 95 CpGs between males with WC ≤ 102 and > 102 cm. These differentially methylated CpGs are located in genes related to inflammation and obesity according to IPA. Receiver operating characteristic (ROC) curves of the top four significant differentially methylated CpGs separated by sex discriminated individuals with presence or absence of abdominal fat. ROC curves of all the CpGs from females and one CpG from males were validated in an independent sample (n = 161). These methylation results add further insights about the relationships between obesity, adiposity-associated comorbidities, and DNA methylation where inflammation processes may be involved. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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Review

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21 pages, 1719 KiB

Open AccessReview

DNA Methylation Dysfunction in Chronic Kidney Disease

by Diego Ingrosso and Alessandra F. Perna

Genes 2020, 11(7), 811; https://doi.org/10.3390/genes11070811 - 16 Jul 2020

Cited by 14 | Viewed by 3772

Abstract

Renal disease is the common denominator of a number of underlying disease conditions, whose prevalence has been dramatically increasing over the last two decades. Two aspects are particularly relevant to the subject of this review: (I) most cases are gathered under the umbrella [...] Read more.

Renal disease is the common denominator of a number of underlying disease conditions, whose prevalence has been dramatically increasing over the last two decades. Two aspects are particularly relevant to the subject of this review: (I) most cases are gathered under the umbrella of chronic kidney disease since they require—predictably for several lustrums—continuous clinical monitoring and treatment to slow down disease progression and prevent complications; (II) cardiovascular disease is a terrible burden in this population of patients, in that it claims many lives yearly, while only a scant minority reach the renal disease end stage. Why indeed a review on DNA methylation and renal disease? As we hope to convince you, the present evidence supports the role of the existence of various derangements of the epigenetic control of gene expression in renal disease, which hold the potential to improve our ability, in the future, to more effectively act toward disease progression, predict outcomes and offer novel therapeutic approaches. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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18 pages, 634 KiB

Open AccessReview

Interplay between Metabolism, Nutrition and Epigenetics in Shaping Brain DNA Methylation, Neural Function and Behavior

by Tommaso Pizzorusso and Paola Tognini

Genes 2020, 11(7), 742; https://doi.org/10.3390/genes11070742 - 03 Jul 2020

Cited by 17 | Viewed by 5526

Abstract

Gene expression in the brain is dramatically regulated by a variety of stimuli. While the role of neural activity has been extensively studied, less is known about the effects of metabolism and nutrition on transcriptional control mechanisms in the brain. Extracellular signals are [...] Read more.

Gene expression in the brain is dramatically regulated by a variety of stimuli. While the role of neural activity has been extensively studied, less is known about the effects of metabolism and nutrition on transcriptional control mechanisms in the brain. Extracellular signals are integrated at the chromatin level through dynamic modifications of epigenetic marks, which in turn fine-tune gene transcription. In the last twenty years, it has become clear that epigenetics plays a crucial role in modulating central nervous system functions and finally behavior. Here, we will focus on the effect of metabolic signals in shaping brain DNA methylation, both during development and adulthood. We will provide an overview of maternal nutrition effects on brain methylation and behavior in offspring. In addition, the impact of different diet challenges on cytosine methylation dynamics in the adult brain will be discussed. Finally, the possible role played by the metabolic status in modulating DNA hydroxymethylation, which is particularly abundant in neural tissue, will be considered. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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18 pages, 2292 KiB

Open AccessReview

DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms

by Loredana Poeta, Denise Drongitis, Lucia Verrillo and Maria Giuseppina Miano

Genes 2020, 11(6), 684; https://doi.org/10.3390/genes11060684 - 22 Jun 2020

Cited by 13 | Viewed by 4909

Abstract

Unstable repeat disorders comprise a variable group of incurable human neurological and neuromuscular diseases caused by an increase in the copy number of tandem repeats located in various regions of their resident genes. It has become clear that dense DNA methylation in hyperexpanded [...] Read more.

Unstable repeat disorders comprise a variable group of incurable human neurological and neuromuscular diseases caused by an increase in the copy number of tandem repeats located in various regions of their resident genes. It has become clear that dense DNA methylation in hyperexpanded non-coding repeats induces transcriptional silencing and, subsequently, insufficient protein synthesis. However, the ramifications of this paradigm reveal a far more profound role in disease pathogenesis. This review will summarize the significant progress made in a subset of non-coding repeat diseases demonstrating the role of dense landscapes of 5-methylcytosine (5mC) as a common disease modifier. However, the emerging findings suggest context-dependent models of 5mC-mediated silencing with distinct effects of excessive DNA methylation. An in-depth understanding of the molecular mechanisms underlying this peculiar group of human diseases constitutes a prerequisite that could help to discover novel pathogenic repeat loci, as well as to determine potential therapeutic targets. In this regard, we report on a brief description of advanced strategies in DNA methylation profiling for the identification of unstable Guanine-Cytosine (GC)-rich regions and on promising examples of molecular targeted therapies for Fragile X disease (FXS) and Friedrich ataxia (FRDA) that could pave the way for the application of this technique in other hypermethylated expansion disorders. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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26 pages, 2245 KiB

Open AccessReview

Epigenetic Factors that Control Pericentric Heterochromatin Organization in Mammals

by Salvatore Fioriniello, Domenico Marano, Francesca Fiorillo, Maurizio D’Esposito and Floriana Della Ragione

Genes 2020, 11(6), 595; https://doi.org/10.3390/genes11060595 - 28 May 2020

Cited by 19 | Viewed by 5547

Abstract

Pericentric heterochromatin (PCH) is a particular form of constitutive heterochromatin that is localized to both sides of centromeres and that forms silent compartments enriched in repressive marks. These genomic regions contain species-specific repetitive satellite DNA that differs in terms of nucleotide sequences and [...] Read more.

Pericentric heterochromatin (PCH) is a particular form of constitutive heterochromatin that is localized to both sides of centromeres and that forms silent compartments enriched in repressive marks. These genomic regions contain species-specific repetitive satellite DNA that differs in terms of nucleotide sequences and repeat lengths. In spite of this sequence diversity, PCH is involved in many biological phenomena that are conserved among species, including centromere function, the preservation of genome integrity, the suppression of spurious recombination during meiosis, and the organization of genomic silent compartments in the nucleus. PCH organization and maintenance of its repressive state is tightly regulated by a plethora of factors, including enzymes (e.g., DNA methyltransferases, histone deacetylases, and histone methyltransferases), DNA and histone methylation binding factors (e.g., MECP2 and HP1), chromatin remodeling proteins (e.g., ATRX and DAXX), and non-coding RNAs. This evidence helps us to understand how PCH organization is crucial for genome integrity. It then follows that alterations to the molecular signature of PCH might contribute to the onset of many genetic pathologies and to cancer progression. Here, we describe the most recent updates on the molecular mechanisms known to underlie PCH organization and function. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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30 pages, 441 KiB

Open AccessReview

DNA Methylation in the Diagnosis of Monogenic Diseases

by Flavia Cerrato, Angela Sparago, Francesca Ariani, Fulvia Brugnoletti, Luciano Calzari, Fabio Coppedè, Alessandro De Luca, Cristina Gervasini, Emiliano Giardina, Fiorella Gurrieri, Cristiana Lo Nigro, Giuseppe Merla, Monica Miozzo, Silvia Russo, Eugenio Sangiorgi, Silvia M Sirchia, Gabriella Maria Squeo, Silvia Tabano, Elisabetta Tabolacci, Isabella Torrente, Maurizio Genuardi, Giovanni Neri and Andrea Riccio Show full author list Hide full author list

Genes 2020, 11(4), 355; https://doi.org/10.3390/genes11040355 - 26 Mar 2020

Cited by 24 | Viewed by 4876

Abstract

DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences [...] Read more.

DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA. The recent use of high-throughput assays investigating the whole genome has largely increased the number of diseases for which DNA methylation analysis provides information for their diagnosis. Here, we review the methylation abnormalities that have been associated with mono/oligogenic diseases, their relationship with genotype and phenotype and relevance for diagnosis, as well as the limitations in their use and interpretation of results. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

19 pages, 1681 KiB

Open AccessReview

Does DNA Methylation Matter in FSHD?

by Valentina Salsi, Frédérique Magdinier and Rossella Tupler

Genes 2020, 11(3), 258; https://doi.org/10.3390/genes11030258 - 28 Feb 2020

Cited by 21 | Viewed by 4362

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable [...] Read more.

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies. On the basis of the reported results we conclude that the percentage of DNA methylation detected at D4Z4 does not correlate with the disease status. Overall, data suggest that in the case of FSHD1, D4Z4 hypomethylation is a consequence of the chromatin structure present in the contracted allele, rather than a proxy of its function. Besides, CpG methylation at D4Z4 DNA is reduced in patients presenting diseases unrelated to muscle progressive wasting, like Bosma Arhinia and Microphthalmia syndrome, a developmental disorder, as well as ICF syndrome. Consistent with these observations, the analysis of epigenetic reprogramming at the D4Z4 locus in human embryonic and induced pluripotent stem cells indicate that other mechanisms, independent from the repeat number, are involved in the control of the epigenetic structure at D4Z4. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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25 pages, 1364 KiB

Open AccessEditor’s ChoiceReview

Understanding the Relevance of DNA Methylation Changes in Immune Differentiation and Disease

by Carlos de la Calle-Fabregat, Octavio Morante-Palacios and Esteban Ballestar

Genes 2020, 11(1), 110; https://doi.org/10.3390/genes11010110 - 18 Jan 2020

Cited by 50 | Viewed by 8244

Abstract

Immune cells are one of the most complex and diverse systems in the human organism. Such diversity implies an intricate network of different cell types and interactions that are dependently interconnected. The processes by which different cell types differentiate from progenitors, mature, and [...] Read more.

Immune cells are one of the most complex and diverse systems in the human organism. Such diversity implies an intricate network of different cell types and interactions that are dependently interconnected. The processes by which different cell types differentiate from progenitors, mature, and finally exert their function requires an orchestrated succession of molecular processes that determine cell phenotype and function. The acquisition of these phenotypes is highly dependent on the establishment of unique epigenetic profiles that confer identity and function on the various types of effector cells. These epigenetic mechanisms integrate microenvironmental cues into the genome to establish specific transcriptional programs. Epigenetic modifications bridge environment and genome regulation and play a role in human diseases by their ability to modulate physiological programs through external stimuli. DNA methylation is one of the most ubiquitous, stable, and widely studied epigenetic modifications. Recent technological advances have facilitated the generation of a vast amount of genome-wide DNA methylation data, providing profound insights into the roles of DNA methylation in health and disease. This review considers the relevance of DNA methylation to immune system cellular development and function, as well as the participation of DNA methylation defects in immune-mediated pathologies, illustrated by selected paradigmatic diseases. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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13 pages, 667 KiB

Open AccessEditor’s ChoiceReview

Pathogenesis of Ischemic Stroke: Role of Epigenetic Mechanisms

by Rosita Stanzione, Maria Cotugno, Franca Bianchi, Simona Marchitti, Maurizio Forte, Massimo Volpe and Speranza Rubattu

Genes 2020, 11(1), 89; https://doi.org/10.3390/genes11010089 - 13 Jan 2020

Cited by 53 | Viewed by 7804

Abstract

Epigenetics is the branch of molecular biology that studies modifications able to change gene expression without altering the DNA sequence. Epigenetic modulations include DNA methylation, histone modifications, and noncoding RNAs. These gene modifications are heritable and modifiable and can be triggered by lifestyle [...] Read more.

Epigenetics is the branch of molecular biology that studies modifications able to change gene expression without altering the DNA sequence. Epigenetic modulations include DNA methylation, histone modifications, and noncoding RNAs. These gene modifications are heritable and modifiable and can be triggered by lifestyle and nutritional factors. In recent years, epigenetic changes have been associated with the pathogenesis of several diseases such as diabetes, obesity, renal pathology, and different types of cancer. They have also been related with the pathogenesis of cardiovascular diseases including ischemic stroke. Importantly, since epigenetic modifications are reversible processes they could assist with the development of new therapeutic approaches for the treatment of human diseases. In the present review article, we aim to collect the most recent evidence concerning the impact of epigenetic modifications on the pathogenesis of ischemic stroke in both animal models and humans. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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16 pages, 793 KiB

Open AccessReview

Cell-Free DNA Methylation: The New Frontiers of Pancreatic Cancer Biomarkers’ Discovery

by Mariarita Brancaccio, Francesco Natale, Geppino Falco and Tiziana Angrisano

Genes 2020, 11(1), 14; https://doi.org/10.3390/genes11010014 - 23 Dec 2019

Cited by 35 | Viewed by 6817

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancer types world-wide. Its high mortality is related to the difficulty in the diagnosis, which often occurs when the disease is already advanced. As of today, no early diagnostic tests are available, while only [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancer types world-wide. Its high mortality is related to the difficulty in the diagnosis, which often occurs when the disease is already advanced. As of today, no early diagnostic tests are available, while only a limited number of prognostic tests have reached clinical practice. The main reason is the lack of reliable biomarkers that are able to capture the early development or the progression of the disease. Hence, the discovery of biomarkers for early diagnosis or prognosis of PDAC remains, de facto, an unmet need. An increasing number of studies has shown that cell-free DNA (cfDNA) methylation analysis represents a promising non-invasive approach for the discovery of biomarkers with diagnostic or prognostic potential. In particular, cfDNA methylation could be utilized for the identification of disease-specific signatures in pre-neoplastic lesions or chronic pancreatitis (CP), representing a sensitive and non-invasive method of early diagnosis of PDAC. In this review, we will discuss the advantages and pitfalls of cfDNA methylation studies. Further, we will present the current advances in the discovery of pancreatic cancer biomarkers with early diagnostic or prognostic potential, focusing on pancreas-specific (e.g., CUX2 or REG1A) or abnormal (e.g., ADAMTS1 or BNC1) cfDNA methylation signatures in high risk pre-neoplastic conditions and PDAC. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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20 pages, 1472 KiB

Open AccessReview

Stability and Lability of Parental Methylation Imprints in Development and Disease

by Sabina Farhadova, Melisa Gomez-Velazquez and Robert Feil

Genes 2019, 10(12), 999; https://doi.org/10.3390/genes10120999 - 02 Dec 2019

Cited by 20 | Viewed by 4967

Abstract

DNA methylation plays essential roles in mammals. Of particular interest are parental methylation marks that originate from the oocyte or the sperm, and bring about mono-allelic gene expression at defined chromosomal regions. The remarkable somatic stability of these parental imprints in the pre-implantation [...] Read more.

DNA methylation plays essential roles in mammals. Of particular interest are parental methylation marks that originate from the oocyte or the sperm, and bring about mono-allelic gene expression at defined chromosomal regions. The remarkable somatic stability of these parental imprints in the pre-implantation embryo—where they resist global waves of DNA demethylation—is not fully understood despite the importance of this phenomenon. After implantation, some methylation imprints persist in the placenta only, a tissue in which many genes are imprinted. Again here, the underlying epigenetic mechanisms are not clear. Mouse studies have pinpointed the involvement of transcription factors, covalent histone modifications, and histone variants. These and other features linked to the stability of methylation imprints are instructive as concerns their conservation in humans, in which different congenital disorders are caused by perturbed parental imprints. Here, we discuss DNA and histone methylation imprints, and why unravelling maintenance mechanisms is important for understanding imprinting disorders in humans. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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