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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 September 2022) | Viewed by 28483

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Dr. Michael Klutstein

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Chromatin and Aging Research Laboratory, Institute of Biomedical and Oral Sciences, Hebrew University of Jerusalem, Jerusalem, Israel
Interests: epigenetics; aging; histone modifications; DNA methylation; fertility; long-term starvation; evolutionary adaptation
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Special Issue Information

Dear Colleagues,

Over the last decade, research regarding topics related to DNA methylation has been developing and expanding. Currently, a description of cellular state is not complete without the complete characterization of the epigenome, of which the most commonly studied and most important aspect is DNA methylation. To advance the field even further, we offer this Special Issue in IJMS, which will collect original research papers and reviews in topics related to DNA methylation and the development of related research.

Dr. Michael Klutstein
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

DNA methylation
DMNT
TET
bisulfite sequencing
RRBS
epigenetics
aging
cancer

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Published Papers (9 papers)

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Research

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20 pages, 2456 KiB

Open AccessArticle

Genome-Wide DNA Methylation Profile Indicates Potential Epigenetic Regulation of Aging in the Rhesus Macaque Thymus

by Hong Qiu, Haobo Li, Ruiwen Fan, Yang Song, Xuan Pan, Chunhui Zhang and Jing Li

Int. J. Mol. Sci. 2022, 23(23), 14984; https://doi.org/10.3390/ijms232314984 - 29 Nov 2022

Cited by 1 | Viewed by 2925

Abstract

We analyzed whole-genome bisulfite sequencing (WGBS) and RNA sequencing data of two young (1 year old) and two adult (9 years old) rhesus macaques (Macaca mulatta) to characterize the genomic DNA methylation profile of the thymus and explore the molecular mechanism of age-related changes in the thymus. Combining the two-omics data, we identified correlations between DNA methylation and gene expression and found that DNA methylation played an essential role in the functional changes of the aging thymus, especially in immunity and coagulation. The hypomethylation levels of C3 and C5AR2 and the hypermethylation level of C7 may lead to the high expressions of these genes in adult rhesus macaque thymuses, thus activating the classical complement pathway and the alternative pathway and enhancing their innate immune function. Adult thymuses had an enhanced coagulation pathway, which may have resulted from the hypomethylation and upregulated expressions of seven coagulation-promoting factor genes (F13A1, CLEC4D, CLEC4E, FCN3, PDGFRA, FGF2 and FGF7) and the hypomethylation and low expression of CPB2 to inhibit the degradation of blood clots. Furthermore, the functional decline in differentiation, activation and maturation of T cells in adult thymuses was also closely related to the changes in methylation levels and gene expression levels of T cell development genes (CD3G, GAD2, ADAMDEC1 and LCK) and the thymogenic hormone gene TMPO. A comparison of the age-related methylated genes among four mammal species revealed that most of the epigenetic clocks were species-specific. Furthermore, based on the genomic landscape of allele-specific DNA methylation, we identified several age-related clustered sequence-dependent allele-specific DNA methylated (cS-ASM) genes. Overall, these DNA methylation patterns may also help to assist with understanding the mechanisms of the aging thymus with the epigenome. Full article

(This article belongs to the Special Issue Advance in the Study of DNA Methylation)

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14 pages, 3767 KiB

Open AccessArticle

Accurate Prediction of Epigenetic Multi-Targets with Graph Neural Network-Based Feature Extraction

by Yishu Wang, Juan Qi and Xiaomin Chen

Int. J. Mol. Sci. 2022, 23(21), 13347; https://doi.org/10.3390/ijms232113347 - 1 Nov 2022

Cited by 3 | Viewed by 2301

Abstract

Epigenetics, referring to genetic modifications that change gene expression, but which are not encoded in DNA, has been shown to be related to oncology, with the potential to influence associated treatments. As such, epigenetic drugs comprise an important new field in cancer therapy; however, drug development is a high-cost and time-consuming procedure. Different epigenetic modifications, such as mutations in DNA methyltransferase and somatic mutations in core histone genes that lead to a global loss of the histone modifications, have innumerable relationships. In this article, we propose a graph neural network-based model for the extraction of molecular features, thus reducing the computational requirements. Through integration with a popular and efficient supervised learner, our model achieves higher prediction accuracy in both single- and multi-target tasks and can determine the pleiotropy associated with drugs, providing theoretical support for drug combination and discovery research. Full article

(This article belongs to the Special Issue Advance in the Study of DNA Methylation)

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22 pages, 3307 KiB

Open AccessArticle

Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

by Amber M. Helliwell, Peter A. Stockwell, Christina D. Edgar, Aniruddha Chatterjee and Warren P. Tate

Int. J. Mol. Sci. 2022, 23(19), 11852; https://doi.org/10.3390/ijms231911852 - 6 Oct 2022

Cited by 12 | Viewed by 3321

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease with variable severity. Patients experience frequent relapses where symptoms increase in severity, leaving them with a marked reduction in quality of life. Previous work has investigated molecular differences between ME/CFS patients and healthy controls, but not the dynamic changes specific to each individual patient. We applied precision medicine here to map genomic changes in two selected ME/CFS patients through a period that contained a relapse recovery cycle. DNA was isolated from two patients and a healthy age/gender matched control at regular intervals and captured the patient relapse in each case. Reduced representation DNA methylation sequencing profiles were obtained spanning the relapse recovery cycle. Both patients showed a significantly larger methylome variability (10–20-fold) through the period of sampling compared with the control. During the relapse, changes in the methylome profiles of the two patients were detected in regulatory-active regions of the genome that were associated, respectively, with 157 and 127 downstream genes, indicating disturbed metabolic, immune and inflammatory functions. Severe health relapses in the ME/CFS patients resulted in functionally important changes in their DNA methylomes that, while differing between the two patients, led to very similar compromised physiology. DNA methylation as a signature of disease variability in ongoing ME/CFS may have practical applications for strategies to decrease relapse frequency. Full article

(This article belongs to the Special Issue Advance in the Study of DNA Methylation)

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15 pages, 2759 KiB

Open AccessArticle

Methodological and Biological Factors Influencing Global DNA Methylation Results Measured by LINE-1 Pyrosequencing Assay in Colorectal Tissue and Liquid Biopsy Samples

by Krisztina A Szigeti, Barbara K Barták, Zsófia B Nagy, Sára Zsigrai, Márton Papp, Eszter Márkus, Peter Igaz, István Takács, Béla Molnár and Alexandra Kalmár

Int. J. Mol. Sci. 2022, 23(19), 11608; https://doi.org/10.3390/ijms231911608 - 1 Oct 2022

Cited by 1 | Viewed by 2137

Abstract

Long interspersed nuclear element 1 (LINE-1) bisulfite pyrosequencing is a widely used technique for genome-wide methylation analyses. We aimed to investigate the effects of experimental and biological factors on its results to improve the comparability. LINE-1 bisulfite pyrosequencing was performed on colorectal tissue (n = 222), buffy coat (n = 39), and plasma samples (n = 9) of healthy individuals and patients with colorectal tumors. Significantly altered methylation was observed between investigated LINE-1 CpG positions of non-tumorous tissues (p ≤ 0.01). Formalin-fixed, paraffin-embedded biopsies (73.0 ± 5.3%) resulted in lower methylation than fresh frozen samples (76.1 ± 2.8%) (p ≤ 0.01). DNA specimens after long-term storage showed higher methylation levels (+3.2%, p ≤ 0.01). In blood collection tubes with preservatives, cfDNA and buffy coat methylation significantly changed compared to K3EDTA tubes (p ≤ 0.05). Lower methylation was detected in older (>40 years, 76.8 ± 1.7%) vs. younger (78.1 ± 1.0%) female patients (p ≤ 0.05), and also in adenomatous tissues with MTHFR 677CT, or 1298AC mutations vs. wild-type (p ≤ 0.05) comparisons. Based on our findings, it is highly recommended to consider the application of standard DNA samples in the case of a possible clinical screening approach, as well as in experimental research studies. Full article

(This article belongs to the Special Issue Advance in the Study of DNA Methylation)

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14 pages, 1986 KiB

Open AccessArticle

Peripheral Blood DNA Methylation Profiles Do Not Predict Endoscopic Post-Operative Recurrence in Crohn’s Disease Patients

by Vincent W. Joustra, Andrew Y. F. Li Yim, Jessica R. de Bruyn, Marjolijn Duijvestein, Ishtu L. Hageman, Wouter J. de Jonge, Peter Henneman, Manon Wildenberg and Geert D’Haens

Int. J. Mol. Sci. 2022, 23(18), 10467; https://doi.org/10.3390/ijms231810467 - 9 Sep 2022

Cited by 3 | Viewed by 2168

Abstract

Prediction of endoscopic post-operative recurrence (POR) in Crohn’s disease (CD) patients following ileocolonic resection (ICR) using clinical risk factors alone has thus far been inadequate. While peripheral blood leukocyte (PBL) DNA methylation has shown promise as a tool for predicting recurrence in cancer, no data in CD patients exists. Therefore, this study explored the association and predictive value of PBL DNA methylation in CD patients following ICR. From a cohort of 117 CD patients undergoing ICR, epigenome-wide PBL methylation profiles from 25 carefully selected patients presenting either clear endoscopic remission (n = 12) or severe recurrence (n = 13) were assessed using the Illumina MethylationEPIC (850K) array. No statistically significant differentially methylated positions (DMPs) or regions (DMRs) associated with endoscopic POR were identified (FDR p ≤ 0.05), further evidenced by the low accuracy (0.625) following elastic net classification analysis. Nonetheless, interrogating the most significant differences in methylation suggested POR-associated hypermethylation in the MBNL1, RAB29 and LEPR genes, respectively, which are involved in intestinal fibrosis, inflammation and wound healing. Notably, we observed a higher estimated proportion of monocytes in endoscopic POR compared to remission. Altogether, we observed limited differences in the genome-wide DNA methylome among CD patients with and without endoscopic POR. We therefore conclude that PBL DNA methylation is not a feasible predictive tool in post-operative CD. Full article

(This article belongs to the Special Issue Advance in the Study of DNA Methylation)

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14 pages, 2499 KiB

Open AccessArticle

Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions

by Dillon T. Lloyd, Harlyn G. Skinner, Rachel Maguire, Susan K. Murphy, Alison A. Motsinger-Reif, Cathrine Hoyo and John S. House

Int. J. Mol. Sci. 2022, 23(18), 10450; https://doi.org/10.3390/ijms231810450 - 9 Sep 2022

Cited by 2 | Viewed by 1873

Abstract

Children conceived with assisted reproductive technology (ART) have an increased risk of adverse outcomes, including congenital malformations and imprinted gene disorders. In a retrospective North Carolina-based-birth-cohort, we examined the effect of ovulation drugs and ART on CpG methylation in differentially methylated CpGs in known imprint control regions (ICRs). Nine ICRs containing 48 CpGs were assessed for methylation status by pyrosequencing in mixed leukocytes from cord blood. After restricting to non-smoking, college-educated participants who agreed to follow-up, ART-exposed (n = 27), clomifene-only-exposed (n = 22), and non-exposed (n = 516) groups were defined. Associations of clomifene and ART with ICR CpG methylation were assessed with linear regression and stratifying by offspring sex. In males, ART was associated with hypomethylation of the PEG3 ICR [β(95% CI) = −1.46 (−2.81, −0.12)] and hypermethylation of the MEG3 ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the NNAT ICR [−5.25 (−10.12, −0.38)]. In female offspring, ART was associated with hypomethylation of the IGF2 ICR [−3.67 (−6.79, −0.55)]. Aberrant methylation of these ICRs has been associated with cardiovascular disease and metabolic and behavioral outcomes in children. The results suggest that the increased risk of adverse outcomes in offspring conceived through ART may be due in part to altered methylation of ICRs. Larger studies utilizing epigenome-wide interrogation are warranted. Full article

(This article belongs to the Special Issue Advance in the Study of DNA Methylation)

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15 pages, 1774 KiB

Open AccessArticle

Significance of Hypermethylation of Tumor-Suppressor Genes PTGER4 and ZNF43 at CpG Sites in the Prognosis of Colorectal Cancer

by Chao-Yang Chen, Jia-Jheng Wu, Yu-Jyun Lin, Chih-Hsiung Hsu, Je-Ming Hu, Pi-Kai Chang, Chien-An Sun, Tsan Yang, Jing-Quan Su and Yu-Ching Chou

Int. J. Mol. Sci. 2022, 23(18), 10225; https://doi.org/10.3390/ijms231810225 - 6 Sep 2022

Cited by 3 | Viewed by 2053

Abstract

The status of DNA methylation in primary tumor tissue and adjacent tumor-free tissue is associated with the occurrence of aggressive colorectal cancer (CRC) and can aid personalized cancer treatments at early stages. Tumor tissue and matched adjacent nontumorous tissue were extracted from 208 patients with CRC, and the correlation between the methylation levels of PTGER4 and ZNF43 at certain CpG loci and the prognostic factors of CRC was determined using the MassARRAY System testing platform. The Wilcoxon signed-rank test, a Chi-square test, and McNemar’s test were used for group comparisons, and Kaplan–Meier curves and a log-rank test were used for prediction. The hypermethylation of PTGER4 at the CpG_4, CpG_5, CpG_15, and CpG_17 tumor tissue sites was strongly correlated with shorter recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) [hazard ratio (HR) = 3.26, 95% confidence interval (CI) = 1.38–7.73 for RFS, HR = 2.35 and 95% CI = 1.17–4.71 for PFS, HR = 4.32 and 95% CI = 1.8–10.5 for OS]. By contrast, RFS and PFS were significantly longer in the case of increased methylation of ZNF43 at the CpG_5 site of normal tissue [HR = 2.33, 95% CI = 1.07–5.08 for RFS, HR = 2.42 and 95% CI = 1.19–4.91 for PFS]. Aberrant methylation at specific CpG sites indicates tissue with aggressive behavior. Therefore, the differential methylation of PTGER4 and ZNF43 at specific loci can be employed for the prognosis of patients with CRC. Full article

(This article belongs to the Special Issue Advance in the Study of DNA Methylation)

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19 pages, 5635 KiB

Open AccessArticle

Early Expression of Tet1 and Tet2 in Mouse Zygotes Altered DNA Methylation Status and Affected Embryonic Development

by Qi Qi, Qianqian Wang, Kailing Liu, Jiangyue Bian, Zhixuan Yu and Jian Hou

Int. J. Mol. Sci. 2022, 23(15), 8495; https://doi.org/10.3390/ijms23158495 - 31 Jul 2022

Cited by 1 | Viewed by 2678

Abstract

Ten-eleven translocation (Tet) dioxygenases can induce DNA demethylation by catalyzing 5-methylcytosine(5mC) to 5-hydroxymethylcytosine(5hmC), and play important roles during mammalian development. In mouse, Tet1 and Tet2 are not expressed in pronucleus-staged embryos and are not involved in the genomic demethylation of early zygotes. Here, we investigated the influence of Tet1 and Tet2 on methylation of parental genomes by ectopically expressing Tet1 and Tet2 in zygotes. Immunofluorescence staining showed a marked 5hmC increase in the maternal pronucleus after injection of Tet1 or Tet2 mRNA into zygotes. Whole-genome bisulfite sequencing further revealed that Tet2 greatly enhanced the global demethylation of both parental genomes, while Tet1 only promoted the paternal demethylation. Tet1 and Tet2 overexpression altered the DNA methylation across genomes, including various genic elements and germline-specific differently methylated regions. Tet2 exhibited overall stronger demethylation activity than Tet1. Either Tet1 or Tet2 overexpression impaired preimplantation embryonic development. These results demonstrated that early expression of Tet1 and Tet2 could substantially alter the zygotic methylation landscape and damage embryonic development. These findings provide new insights into understanding the function of Tet dioxygenases and the mechanism of DNA methylation in relation to embryogenesis. Full article

(This article belongs to the Special Issue Advance in the Study of DNA Methylation)

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25 pages, 2542 KiB

Open AccessReview

Epigenetics and Pregnancy: Conditional Snapshot or Rolling Event

by Mariana Andrawus, Lital Sharvit and Gil Atzmon

Int. J. Mol. Sci. 2022, 23(20), 12698; https://doi.org/10.3390/ijms232012698 - 21 Oct 2022

Cited by 12 | Viewed by 7341

Abstract

Epigenetics modification such as DNA methylation can affect maternal health during the gestation period. Furthermore, pregnancy can drive a range of physiological and molecular changes that have the potential to contribute to pathological conditions. Pregnancy-related risk factors include multiple environmental, behavioral, and hereditary factors that can impact maternal DNA methylation with long-lasting consequences. Identification of the epigenetic patterns linked to poor pregnancy outcomes is crucial since changes in DNA methylation patterns can have long-term effects. In this review, we provide an overview of the epigenetic changes that influence pregnancy-related molecular programming such as gestational diabetes, immune response, and pre-eclampsia, in an effort to close the gap in current understanding regarding interactions between the environment, the genetics of the fetus, and the pregnant woman. Full article

(This article belongs to the Special Issue Advance in the Study of DNA Methylation)

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