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DNA Methylation in Human Diseases

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Nucleic Acids".

Deadline for manuscript submissions: closed (15 August 2024) | Viewed by 23661

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Dr. Eleonora Loi

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Department of Biomedical Sciences, University of Cagliari, 09042 Cagliari, Italy
Interests: DNA methylation alterations; bioinformatic analysis of genomic and epigenomic data; epigenome editing; 2D and 3D cellular models; epigenomics
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Dr. Patrizia Zavattari

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Department of Biomedical Sciences, University of Cagliari, 09042 Cagliari, Italy
Interests: DNA methylation alterations; somatic mutations and epimutations in solid and blood cancers; genomics; epigenomics; genetics of complex traits; trace elements and multifactorial diseases
Special Issues, Collections and Topics in MDPI journals

Dr. Ana Florencia Vega Benedetti

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Department of Biomedical Sciences, University of Cagliari, 09042 Cagliari, Italy
Interests: DNA methylation alterations; iPSC generation and cellular differentiation; 3D cellular models; solid tumors; infectious diseases

Special Issue Information

Dear Colleagues,

DNA methylation plays a crucial role in many biological processes, contributing to gene expression regulation. A growing body of evidence underlines that DNA methylation alterations are associated with several human diseases, including cancer, imprinting disorders, metabolic disorders, infectious diseases, autoimmune diseases, neurological disorders and others. Defects in the machinery that regulates the establishment and the maintenance of DNA methylation pattern can give rise to gene expression changes, leading to the onset of human diseases and influence their clinical course. Therefore, DNA methylation changes can be used as biomarkers at all stages of clinical disease management, from risk assessment, early diagnosis, prognosis, treatment choice and relapse monitoring. Furthermore, given the reversible nature of epigenetic modifications, there is an increasing interest in developing methods to reverse DNA methylation aberrations.

This Special Issue welcomes contributions focused on the role of DNA methylation in human diseases, including, but not limited to, studies aimed at elucidating the mechanisms leading to DNA methylation aberrations, understanding the functional impact of DNA methylation changes, the discovery of potential DNA methylation biomarkers and the development of new therapies based on DNA methylation reprogramming.

Dr. Eleonora Loi
Dr. Patrizia Zavattari
Dr. Ana Florencia Vega Benedetti
Guest Editors

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Keywords

DNA methylation alterations
DNA methylation profiling
DNMT aberrations
TET aberrations
DNA methylation machinery
DNA methylation biomarkers
DNA methylation reprogramming

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Published Papers (12 papers)

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Research

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12 pages, 1405 KiB

Open AccessArticle

NALCN Promoter Methylation as a Biomarker for Metastatic Risk in a Cohort of Non-Small Cell Lung Cancer Patients

by Eleni Thanou, Dora Lontra, Ioanna Balgouranidou, Eleni Efthimiadou, Alexandra Delipetrou, Emilia Tsaroucha, Maria Theodosiou, Vassilis Georgoulias, Athanasios Kotsakis, Evi Lianidou and Athina Markou

Biomolecules 2024, 14(12), 1514; https://doi.org/10.3390/biom14121514 - 27 Nov 2024

Viewed by 558

Abstract

Liquid biopsy enables real-time monitoring of tumor development and response to therapy through the analysis of CTCs and ctDNA. NALCN is a sodium leak channel that is frequently involved in tumor evolution and immunity and acts as a tumor suppressor. Deletion of NALCN has been shown to increase cancer metastasis and the number of CTCs in peripheral blood. In this study, we investigated for the first time NALCN promoter methylation in (a) Aza-treated cell lines (A549, TE671, BT20, and MDA-MB-468), (b) paired NSCLC tissues (n = 22), and (c) plasma cell-free DNA (ctDNA) from patients with NSCLC (early stage n = 39, metastatic n = 39) and DNA from 10 healthy donors (HD) using a newly developed highly specific and sensitive real-time MSP method. Treatment with 5′-aza-dC induced the expression of NALCN only in the A549 cell line, suggesting that DNA methylation regulates its expression in certain cancers. The mRNA expression levels of NALCN were quantified in non-small cell lung cancer (NSCLC) and adjacent non-cancerous tissues, and it was found to be underexpressed in 54.5% of tumor tissues, with significantly higher expression in recurrence-free patients (p = 0.009) than in patients who relapsed. The NALCN methylation level was not statisticallysignificantlycorrelated with the corresponding expression (p = 0.439), while Kaplan–Meier analysis showed an association between NALCN promoter hypermethylation and worse disease-free intervals (DFIs) (p = 0.017). Evaluation of NALCN methylation in ctDNA revealed that it was detected in 5.1% of early and 10.2% of advanced cases. Our results strongly suggest that epigenetic inactivation of NALCN may be a predictor of metastasis in NSCLC. Our results should be validated in further studies based on a larger patient cohort to further investigate whether DNA methylation of the NALCN promoter could serve as a potential prognostic DNA methylation biomarker and predictor of metastasis in NSCLC. Full article

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

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14 pages, 2043 KiB

Open AccessArticle

Discovery and Validation of Methylation Signatures in Circulating Cell-Free DNA for the Detection of Colorectal Cancer

by Zhiping Long, Yu Gao, Zhen Han, Heli Yuan, Yue Yu, Bing Pei, Yanjie Jia, Jingyu Ye, Ying Shi, Min Zhang, Yashuang Zhao, Di Wu and Fan Wang

Biomolecules 2024, 14(8), 996; https://doi.org/10.3390/biom14080996 - 13 Aug 2024

Viewed by 1513

Abstract

This study was conducted with the primary objective of assessing the performance of cfDNA methylation in the detection of colorectal cancer (CRC). Five tumor tissue, 20 peripheral blood leucocyte, and 169 cfDNA samples were collected for whole-genome bisulfite sequencing (WGBS) analysis. Bioinformatic analysis was conducted to identify differentially methylated regions (DMRs) and their functional characteristics. Quantitative methylation-specific PCR (qMSP) was used to validate the methylation levels of DMRs in the tissues and leucocytes. cfDNA samples from CRC patients and healthy controls were used to evaluate the performance of the DMR analysis. WGBS analysis revealed a decrease in DNA methylation levels in the CpG context in CRC tumor tissues compared with adjacent normal tissues. A total of 132 DMRs in cfDNA were identified as potential markers for diagnosing CRC. In a cohort of 95 CRC patients and 74 healthy controls, a combination of the three DMRs (DAB1, PPP2R5C, and FAM19A5) yielded an AUC of 0.763, achieving 64.21% sensitivity and 78.38% specificity in discriminating CRC patients from healthy controls. This study provides insights into DNA methylation patterns in CRC and identifies a set of DMRs in cfDNA with potential diagnostic value for CRC. These DMRs hold promise as biomarkers for CRC detection, offering promise for non-invasive CRC diagnosis. Further research is warranted to validate these findings in larger cohorts. Full article

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

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18 pages, 3012 KiB

Open AccessEditor’s ChoiceArticle

Smoking-Induced DNA Hydroxymethylation Signature Is Less Pronounced than True DNA Methylation: The Population-Based KORA Fit Cohort

by Liye Lai, Pamela R. Matías-García, Anja Kretschmer, Christian Gieger, Rory Wilson, Jakob Linseisen, Annette Peters and Melanie Waldenberger

Biomolecules 2024, 14(6), 662; https://doi.org/10.3390/biom14060662 - 5 Jun 2024

Viewed by 1307

Abstract

Despite extensive research on 5-methylcytosine (5mC) in relation to smoking, there has been limited exploration into the interaction between smoking and 5-hydroxymethylcytosine (5hmC). In this study, total DNA methylation (5mC+5hmC), true DNA methylation (5mC) and hydroxymethylation (5hmC) levels were profiled utilizing conventional bisulphite (BS) and oxidative bisulphite (oxBS) treatment, measured with the Illumina Infinium Methylation EPIC BeadChip. An epigenome-wide association study (EWAS) of 5mC+5hmC methylation revealed a total of 38,575 differentially methylated positions (DMPs) and 2023 differentially methylated regions (DMRs) associated with current smoking, along with 82 DMPs and 76 DMRs associated with former smoking (FDR-adjusted p < 0.05). Additionally, a focused examination of 5mC identified 33 DMPs linked to current smoking and 1 DMP associated with former smoking (FDR-adjusted p < 0.05). In the 5hmC category, eight DMPs related to current smoking and two DMPs tied to former smoking were identified, each meeting a suggestive threshold (p < 1 × 10⁻⁵). The substantial number of recognized DMPs, including 5mC+5hmC (7069/38,575, 2/82), 5mC (0/33, 1/1), and 5hmC (2/8, 0/2), have not been previously reported. Our findings corroborated previously established methylation positions and revealed novel candidates linked to tobacco smoking. Moreover, the identification of hydroxymethylated CpG sites with suggestive links provides avenues for future research. Full article

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

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21 pages, 610 KiB

Open AccessArticle

Identifying Differential Methylation in Cancer Epigenetics via a Bayesian Functional Regression Model

by Farhad Shokoohi, David A. Stephens and Celia M. T. Greenwood

Biomolecules 2024, 14(6), 639; https://doi.org/10.3390/biom14060639 - 29 May 2024

Cited by 1 | Viewed by 1272

Abstract

DNA methylation plays an essential role in regulating gene activity, modulating disease risk, and determining treatment response. We can obtain insight into methylation patterns at a single-nucleotide level via next-generation sequencing technologies. However, complex features inherent in the data obtained via these technologies pose challenges beyond the typical big data problems. Identifying differentially methylated cytosines (dmc) or regions is one such challenge. We have developed DMCFB, an efficient dmc identification method based on Bayesian functional regression, to tackle these challenges. Using simulations, we establish that DMCFB outperforms current methods and results in better smoothing and efficient imputation. We analyzed a dataset of patients with acute promyelocytic leukemia and control samples. With DMCFB, we discovered many new dmcs and, more importantly, exhibited enhanced consistency of differential methylation within islands and their adjacent shores. Additionally, we detected differential methylation at more of the binding sites of the fused gene involved in this cancer. Full article

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

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19 pages, 6791 KiB

Open AccessArticle

Hypermethylation of the Gene Body in SRCIN1 Is Involved in Breast Cancer Cell Proliferation and Is a Potential Blood-Based Biomarker for Early Detection and a Poor Prognosis

by Hsieh-Tsung Shen, Chin-Sheng Hung, Clilia Davis, Chih-Ming Su, Li-Min Liao, Hsiu-Ming Shih, Kuan-Der Lee, Muhamad Ansar and Ruo-Kai Lin

Biomolecules 2024, 14(5), 571; https://doi.org/10.3390/biom14050571 - 12 May 2024

Viewed by 2482

Abstract

Breast cancer is a leading cause of cancer mortality in women worldwide. Using the Infinium MethylationEPIC BeadChip, we analyzed plasma sample methylation to identify the SRCIN1 gene in breast cancer patients. We assessed SRCIN1-related roles and pathways for their biomarker potential. To verify the methylation status, quantitative methylation-specific PCR (qMSP) was performed on genomic DNA and circulating cell-free DNA samples, and mRNA expression analysis was performed using RT‒qPCR. The results were validated in a Western population; for this analysis, the samples included plasma samples from breast cancer patients from the USA and from The Cancer Genome Atlas (TCGA) cohort. To study the SRCIN1 pathway, we conducted cell viability assays, gene manipulation and RNA sequencing. SRCIN1 hypermethylation was identified in 61.8% of breast cancer tissues from Taiwanese patients, exhibiting specificity to this malignancy. Furthermore, its presence correlated significantly with unfavorable 5-year overall survival outcomes. The levels of methylated SRCIN1 in the blood of patients from Taiwan and the USA correlated with the stage of breast cancer. The proportion of patients with high methylation levels increased from 0% in healthy individuals to 63.6% in Stage 0, 80% in Stage I and 82.6% in Stage II, with a sensitivity of 78.5%, an accuracy of 90.3% and a specificity of 100%. SRCIN1 hypermethylation was significantly correlated with increased SRCIN1 mRNA expression (p < 0.001). Knockdown of SRCIN1 decreased the viability of breast cancer cells. SRCIN1 silencing resulted in the downregulation of ESR1, BCL2 and various cyclin protein expressions. SRCIN1 hypermethylation in the blood may serve as a noninvasive biomarker, facilitating early detection and prognosis evaluation, and SRCIN1-targeted therapies could be used in combination regimens for breast cancer patients. Full article

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

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16 pages, 5050 KiB

Open AccessArticle

Nicotinic Acid-Mediated Modulation of Metastasis-Associated Protein 1 Methylation and Inflammation in Brain Arteriovenous Malformation

by Xinpeng Deng, Shengjun Zhou, Ziliang Hu, Fanyong Gong, Junjun Zhang, Chenhui Zhou, Wenting Lan, Xiang Gao and Yi Huang

Biomolecules 2023, 13(10), 1495; https://doi.org/10.3390/biom13101495 - 8 Oct 2023

Viewed by 2459

Abstract

We explored metastasis-associated protein 1 (MTA1) promoter methylation in the development of brain arteriovenous malformation (BAVM). The clinical data of 148 sex- and age-matched BAVMs and controls were collected, and the MTA1 DNA methylation in peripheral white blood cells (WBC) was assessed by bisulfite pyrosequencing. Among them, 18 pairs of case–control samples were used for WBC mRNA detection, 32 pairs were used for WBC MTA1 protein measurement, and 50 pairs were used for plasma inflammatory factor analysis. Lipopolysaccharide (LPS) treatment was used to induce an inflammatory injury cell model of human brain microvascular endothelial cells (BMECS). 5-Aza-2′-deoxycytidine (5-AZA), nicotinic acid (NA), and MTA1 siRNAs were used in functional experiments to examine BMECS behaviors. RT-qPCR, Western blot, and ELISA or cytometric bead arrays were used to measure the expression levels of MTA1, cytokines, and signaling pathway proteins in human blood or BMECS. The degree of MTA1 promoter methylation was reduced in BAVM compared with the control group and was inversely proportional to MTA1 expression. Plasma ApoA concentrations in BAVM patients were significantly lower than those in controls and correlated positively with MTA1 promoter methylation and negatively with MTA1 expression. The expression of cytokine was markedly higher in BAVM than in controls. Cell experiments showed that 5-AZA decreased the methylation level of MTA1 and increased the expression of MTA1 protein. LPS treatment significantly increased cytokine concentrations (p < 0.05). NA and MTA1 silencing could effectively reverse the LPS-mediated increase in IL-6 and TNF-α expression through the NF-κB pathway. Our study indicated that NA may regulate MTA1 expression by affecting promoter DNA methylation, improve vascular inflammation through the NF-κB pathway, and alleviate the pathological development of BAVM. Full article

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

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Review

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23 pages, 1766 KiB

Open AccessReview

Exposure to Metals, Pesticides, and Air Pollutants: Focus on Resulting DNA Methylation Changes in Neurodegenerative Diseases

by Andrea Stoccoro and Fabio Coppedè

Biomolecules 2024, 14(11), 1366; https://doi.org/10.3390/biom14111366 - 27 Oct 2024

Viewed by 1534

Abstract

Individuals affected by neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), are dramatically increasing worldwide. Thus, several efforts are being made to develop strategies for stopping or slowing the spread of these illnesses. Although causative genetic variants linked to the onset of these diseases are known, they can explain only a small portion of cases. The etiopathology underlying the neurodegenerative process in most of the patients is likely due to the interplay between predisposing genetic variants and environmental factors. Epigenetic mechanisms, including DNA methylation, are central candidates in translating the effects of environmental factors in genome modulation, and they play a critical role in the etiology of AD, PD, and ALS. Among the main environmental exposures that have been linked to an increased risk for these diseases, accumulating evidence points to the role of heavy metals, pesticides, and air pollutants. These compounds could trigger neurodegeneration through different mechanisms, mainly neuroinflammation and the induction of oxidative stress. However, increasing evidence suggests that they are also capable of inducing epigenetic alterations in neurons. In this article, we review the available literature linking exposure to metals, pesticides, and air pollutants to DNA methylation changes relevant to neurodegeneration. Full article

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

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36 pages, 6145 KiB

Open AccessReview

Methods for Detection and Mapping of Methylated and Hydroxymethylated Cytosine in DNA

by Olga Kisil, Alexander Sergeev, Anna Bacheva and Maria Zvereva

Biomolecules 2024, 14(11), 1346; https://doi.org/10.3390/biom14111346 - 23 Oct 2024

Viewed by 1279

Abstract

The chemical modifications of DNA are of pivotal importance in the epigenetic regulation of cellular processes. Although the function of 5-methylcytosine (5mC) has been extensively investigated, the significance of 5-hydroxymethylcytosine (5hmC) has only recently been acknowledged. Conventional methods for the detection of DNA methylation frequently lack the capacity to distinguish between 5mC and 5hmC, resulting in the combined reporting of both. The growing importance of 5hmC has prompted the development of a multitude of methods for the qualitative and quantitative analysis of 5hmC in recent years, thereby facilitating researchers’ understanding of the mechanisms underlying the onset and progression of numerous diseases. This review covers both established and novel methods for the detection of cytosine modifications, including 5mC, 5hmC, 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), with a particular focus on those that allow for accurate mapping and detection, particularly with third-generation sequencing. The review aims to help researchers choose the most appropriate methods based on their specific research goals and budget. Full article

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

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16 pages, 774 KiB

Open AccessReview

DNA Methylation as a Molecular Mechanism of Carcinogenesis in World Trade Center Dust Exposure: Insights from a Structured Literature Review

by Stephanie Tuminello, Nedim Durmus, Matija Snuderl, Yu Chen, Yongzhao Shao, Joan Reibman, Alan A. Arslan and Emanuela Taioli

Biomolecules 2024, 14(10), 1302; https://doi.org/10.3390/biom14101302 - 15 Oct 2024

Viewed by 1195

Abstract

The collapse of the World Trade Center (WTC) buildings in New York City generated a large plume of dust and smoke. WTC dust contained human carcinogens including metals, asbestos, polycyclic aromatic hydrocarbons (PAHs), persistent organic pollutants (POPs, including polychlorinated biphenyls (PCBs) and dioxins), and benzene. Excess levels of many of these carcinogens have been detected in biological samples of WTC-exposed persons, for whom cancer risk is elevated. As confirmed in this structured literature review (n studies = 80), all carcinogens present in the settled WTC dust (metals, asbestos, benzene, PAHs, POPs) have previously been shown to be associated with DNA methylation dysregulation of key cancer-related genes and pathways. DNA methylation is, therefore, a likely molecular mechanism through which WTC exposures may influence the process of carcinogenesis. Full article

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

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22 pages, 1541 KiB

Open AccessReview

The Role of DNMT Methyltransferases and TET Dioxygenases in the Maintenance of the DNA Methylation Level

by Anastasiia T. Davletgildeeva and Nikita A. Kuznetsov

Biomolecules 2024, 14(9), 1117; https://doi.org/10.3390/biom14091117 - 4 Sep 2024

Cited by 2 | Viewed by 1650

Abstract

This review deals with the functional characteristics and biological roles of enzymes participating in DNA methylation and demethylation as key factors in epigenetic regulation of gene expression. The set of enzymes that carry out such processes in human cells is limited to representatives of two families, namely DNMT (DNA methyltransferases) and TET (DNA dioxygenases). The review presents detailed information known today about each functionally important member of these families and describes the catalytic activity and roles in the mammalian body while also providing examples of dysregulation of the expression and/or activity of these enzymes in conjunction with the development of some human disorders, including cancers, neurodegenerative diseases, and developmental pathologies. By combining the up-to-date information on the dysfunction of various enzymes that control the DNA “methylome” in the human body, we hope not only to draw attention to the importance of the maintenance of a required DNA methylation level (ensuring epigenetic regulation of gene expression and normal functioning of the entire body) but also to help identify new targets for directed control over the activity of the enzymes that implement the balance between processes of DNA methylation and demethylation. Full article

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

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14 pages, 1357 KiB

Open AccessReview

Biological Rhythms, Chrono-Nutrition, and Gut Microbiota: Epigenomics Insights for Precision Nutrition and Metabolic Health

by Nathalia Caroline de Oliveira Melo, Amanda Cuevas-Sierra, Vitória Felício Souto and J. Alfredo Martínez

Biomolecules 2024, 14(5), 559; https://doi.org/10.3390/biom14050559 - 6 May 2024

Cited by 3 | Viewed by 3814

Abstract

Circadian rhythms integrate a finely tuned network of biological processes recurring every 24 h, intricately coordinating the machinery of all cells. This self-regulating system plays a pivotal role in synchronizing physiological and behavioral responses, ensuring an adaptive metabolism within the environmental milieu, including dietary and physical activity habits. The systemic integration of circadian homeostasis involves a balance of biological rhythms, each synchronically linked to the central circadian clock. Central to this orchestration is the temporal dimension of nutrient and food intake, an aspect closely interwoven with the neuroendocrine circuit, gut physiology, and resident microbiota. Indeed, the timing of meals exerts a profound influence on cell cycle regulation through genomic and epigenetic processes, particularly those involving gene expression, DNA methylation and repair, and non-coding RNA activity. These (epi)genomic interactions involve a dynamic interface between circadian rhythms, nutrition, and the gut microbiota, shaping the metabolic and immune landscape of the host. This research endeavors to illustrate the intricate (epi)genetic interplay that modulates the synchronization of circadian rhythms, nutritional signaling, and the gut microbiota, unravelling the repercussions on metabolic health while suggesting the potential benefits of feed circadian realignment as a non-invasive therapeutic strategy for systemic metabolic modulation via gut microbiota. This exploration delves into the interconnections that underscore the significance of temporal eating patterns, offering insights regarding circadian rhythms, gut microbiota, and chrono-nutrition interactions with (epi)genomic phenomena, thereby influencing diverse aspects of metabolic, well-being, and quality of life outcomes. Full article

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

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21 pages, 6812 KiB

Open AccessReview

Transgenerational Epigenetic DNA Methylation Editing and Human Disease

by Joshua D. Tompkins

Biomolecules 2023, 13(12), 1684; https://doi.org/10.3390/biom13121684 - 22 Nov 2023

Cited by 1 | Viewed by 2356

Abstract

During gestation, maternal (F0), embryonic (F1), and migrating primordial germ cell (F2) genomes can be simultaneously exposed to environmental influences. Accumulating evidence suggests that operating epi- or above the genetic DNA sequence, covalent DNA methylation (DNAme) can be recorded onto DNA in response to environmental insults, some sites which escape normal germline erasure. These appear to intrinsically regulate future disease propensity, even transgenerationally. Thus, an organism’s genome can undergo epigenetic adjustment based on environmental influences experienced by prior generations. During the earliest stages of mammalian development, the three-dimensional presentation of the genome is dramatically changed, and DNAme is removed genome wide. Why, then, do some pathological DNAme patterns appear to be heritable? Are these correctable? In the following sections, I review concepts of transgenerational epigenetics and recent work towards programming transgenerational DNAme. A framework for editing heritable DNAme and challenges are discussed, and ethics in human research is introduced. Full article

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

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