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

Deadline for manuscript submissions: closed (31 December 2017) | Viewed by 81932

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Prof. Dr. Reinhard Dammann

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Guest Editor

Institute for Genetics, Justus-Liebig-University Giessen, Heinrich Buff Ring 58-62, Giessen D-35392, Germany
Interests: RASSF signalling; DNA methylation in cancer
Special Issues, Collections and Topics in MDPI journals

Assoc. Prof. Alexander Dobrovic

E-Mail Website1 Website2
Guest Editor

Olivia Newton-John Cancer Research Institute, Heidelberg (Melbourne), Victoria 3084, Australia
Interests: translational; genomics; epigenetics

Special Issue Information

Dear Colleagues,

Methylation of cytosine is a long-term epigenetic modification of the genome. Epigenetic deregulation of genes is achieved by aberrant DNA methylation of promoter sequences in different human malignancies, including cancer. The discovery of proteins that oxidase 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) has extended our knowledge of how aberrant DNA methylation is coupled to gene regulation in cancer and other human malignancies. Current models propose that 5hmC is an intermediate base in the DNA demethylation process, or a bivalent chromatin marker found in cancer and stem cells.

In this Special Issue of IJMS we invite you to submit an original research report or review article deciphering the role of DNA methylation in malignancies, aging or differentiation.

Prof. Dr. Reinhard Dammann
Assoc. Prof. Alexander Dobrovic
Guest Editors

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Keywords

5-methyl-cytosine
5-hydroxymethyl-cytosine
biomarker
cancer

Published Papers (12 papers)

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Research

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20 pages, 1867 KiB

Open AccessArticle

DNA Methylation Profiling of Breast Cancer Cell Lines along the Epithelial Mesenchymal Spectrum—Implications for the Choice of Circulating Tumour DNA Methylation Markers

by Anh Viet-Phuong Le, Marcin Szaumkessel, Tuan Zea Tan, Jean-Paul Thiery, Erik W. Thompson and Alexander Dobrovic

Int. J. Mol. Sci. 2018, 19(9), 2553; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092553 - 28 Aug 2018

Cited by 17 | Viewed by 5454

Abstract

(1) Background: Epithelial–mesenchymal plasticity (EMP) is a dynamic process whereby epithelial carcinoma cells reversibly acquire morphological and invasive characteristics typical of mesenchymal cells. Identifying the methylation differences between epithelial and mesenchymal states may assist in the identification of optimal DNA methylation biomarkers for the blood-based monitoring of cancer. (2) Methods: Methylation-sensitive high-resolution melting (MS-HRM) was used to examine the promoter methylation status of a panel of established and novel markers in a range of breast cancer cell lines spanning the epithelial–mesenchymal spectrum. Pyrosequencing was used to validate the MS-HRM results. (3) Results: VIM, DKK3, and CRABP1 were methylated in the majority of epithelial breast cancer cell lines, while methylation of GRHL2, MIR200C, and CDH1 was restricted to mesenchymal cell lines. Some markers that have been used to assess minimal residual disease such as AKR1B1 and APC methylation proved to be specific for epithelial breast cell lines. However, RASSF1A, RARβ, TWIST1, and SFRP2 methylation was seen in both epithelial and mesenchymal cell lines, supporting their suitability for a multimarker panel. (4) Conclusions: Profiling DNA methylation shows a distinction between epithelial and mesenchymal phenotypes. Understanding how DNA methylation varies between epithelial and mesenchymal phenotypes may lead to more rational selection of methylation-based biomarkers for circulating tumour DNA analysis. Full article

(This article belongs to the Special Issue DNA Methylation)

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16 pages, 1764 KiB

Open AccessArticle

Memory Function in Feeding Habit Transformation of Mandarin Fish (Siniperca chuatsi)

by Yaqi Dou, Shan He, Xu-Fang Liang, Wenjing Cai, Jie Wang, Linjie Shi and Jiao Li

Int. J. Mol. Sci. 2018, 19(4), 1254; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19041254 - 22 Apr 2018

Cited by 16 | Viewed by 5773

Abstract

Mandarin fish refuse dead prey fish or artificial diets and can be trained to transform their inborn feeding habit. To investigate the effect of memory on feeding habit transformation, we compared the reaction time to dead prey fish and the success rate of feeding habit transformation to dead prey fish with training of mandarin fish in the 1st experimental group (trained once) and the 2nd experimental group (trained twice). The mandarin fish in the 2nd group had higher success rate of feeding habit transformation (100%) than those in the 1st group (67%), and shorter reaction time to dead prey fish (<1 s) than those in the 1st group (>1 s). Gene expression of cAMP responsive element binding protein I (Creb I), brain-derived neurotrophic factor (Bdnf), CCAAT enhancer binding protein delta (C/EBPD), fos-related antigen 2 (Fra2), and proto-oncogenes c-fos (c-fos) involved in long-term memory formation were significantly increased in the 2nd group after repeated training, and taste 1 receptor member 1 (T1R1), involved in feeding habit formation, was significantly increased in brains of the 2nd group after repeated training. DNA methylation levels at five candidate CpG (cytosine–guanine) sites contained in the predicted CpG island in the 5′-flanking region of T1R1 were significantly decreased in brains of the 2nd group compared with that of the 1st group. These results indicated that the repeated training can improve the feeding habit transformation through the memory formation of accepting dead prey fish. DNA methylation of the T1R1 might be a regulatory factor for feeding habit transformation from live prey fish to dead prey fish in mandarin fish. Full article

(This article belongs to the Special Issue DNA Methylation)

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17 pages, 26585 KiB

Open AccessArticle

Cell-Specific PEAR1 Methylation Studies Reveal a Locus that Coordinates Expression of Multiple Genes

by Benedetta Izzi, Fabrizia Noro, Katrien Cludts, Kathleen Freson and Marc F. Hoylaerts

Int. J. Mol. Sci. 2018, 19(4), 1069; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19041069 - 03 Apr 2018

Cited by 10 | Viewed by 4136

Abstract

Chromosomal interactions connect distant enhancers and promoters on the same chromosome, activating or repressing gene expression. PEAR1 encodes the Platelet-Endothelial Aggregation Receptor 1, a contact receptor involved in platelet function and megakaryocyte and endothelial cell proliferation. PEAR1 expression during megakaryocyte differentiation is controlled by DNA methylation at its first CpG island. We identified a PEAR1 cell-specific methylation sensitive region in endothelial cells and megakaryocytes that showed strong chromosomal interactions with ISGL20L2, RRNAD1, MRLP24, HDGF and PRCC, using available promoter capture Hi-C datasets. These genes are involved in ribosome processing, protein synthesis, cell cycle and cell proliferation. We next studied the methylation and expression profile of these five genes in Human Umbilical Vein Endothelial Cells (HUVECs) and megakaryocyte precursors. While cell-specific PEAR1 methylation corresponded to variability in expression for four out of five genes, no methylation change was observed in their promoter regions across cell types. Our data suggest that PEAR1 cell-type specific methylation changes may control long distance interactions with other genes. Further studies are needed to show whether such interaction data might be relevant for the genome-wide association data that showed a role for non-coding PEAR1 variants in the same region and platelet function, platelet count and cardiovascular risk. Full article

(This article belongs to the Special Issue DNA Methylation)

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12 pages, 279 KiB

Open AccessArticle

Evaluation of Promoter Methylation of RASSF1A and ATM in Peripheral Blood of Breast Cancer Patients and Healthy Control Individuals

by Xue Cao, Qiuqiong Tang, Tim Holland-Letz, Melanie Gündert, Katarina Cuk, Sarah Schott, Jörg Heil, Michael Golatta, Christof Sohn, Andreas Schneeweiss and Barbara Burwinkel

Int. J. Mol. Sci. 2018, 19(3), 900; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19030900 - 19 Mar 2018

Cited by 17 | Viewed by 4292

Abstract

Breast cancer (BC) is the most common cancer among women and has high mortality rates. Early detection is supposed to be critical for the patient’s prognosis. In recent years, several studies have investigated global DNA methylation profiles and gene-specific DNA methylation in blood-based DNA to develop putative screening markers for cancer. However, most of the studies have not yet been validated. In our study, we analyzed the promoter methylation of RASSF1A and ATM in peripheral blood DNA of 229 sporadic patients and 151 healthy controls by the MassARRAY EpiTYPER assay. There were no significant differences in DNA methylation levels of RASSF1A and ATM between the sporadic BC cases and the healthy controls. Furthermore, we performed the Infinium HumanMethylation450 BeadChip (450K) array analysis using 48 sporadic BC cases and 48 healthy controls (cases and controls are the same from those of the MassARRAY EpiTYPER assay) and made a comparison with the published data. No significant differences were presented in DNA methylation levels of RASSF1A and ATM between the sporadic BC cases and the healthy controls. So far, the evidence for powerful blood-based methylation markers is still limited and the identified markers need to be further validated. Full article

(This article belongs to the Special Issue DNA Methylation)

13 pages, 2163 KiB

Open AccessArticle

DNA Methylation Levels of the ELMO Gene Promoter CpG Islands in Human Glioblastomas

by Signe Regner Michaelsen, Derya Aslan, Thomas Urup, Hans Skovgaard Poulsen, Kirsten Grønbæk, Helle Broholm and Lasse Sommer Kristensen

Int. J. Mol. Sci. 2018, 19(3), 679; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19030679 - 28 Feb 2018

Cited by 10 | Viewed by 4471

Abstract

Complete surgical resection of glioblastoma is difficult due to the invasive nature of this primary brain tumor, for which the molecular mechanisms behind remain poorly understood. The three human ELMO genes play key roles in cellular motility, and have been linked to metastasis and poor prognosis in other cancer types. The aim of this study was to investigate methylation levels of the ELMO genes and their correlation to clinical characteristics and outcome in patients diagnosed with glioblastoma. To measure DNA methylation levels we designed pyrosequencing assays targeting the promoter CpG island of each the ELMO genes. These were applied to diagnostic tumor specimens from a well-characterized cohort of 121 patients who received standard treatment consisting of surgery, radiation therapy, plus concomitant and adjuvant chemotherapy. The promoter methylation levels of ELMO1 and ELMO2 were generally low, whereas ELMO3 methylation levels were high, in the tumor biopsies. Thirteen, six, and 18 biopsies were defined as aberrantly methylated for ELMO1, ELMO2, and ELMO3, respectively. There were no significant associations between the methylation status of any of the ELMO gene promoter CpG islands and overall survival, progression-free survival, and clinical characteristics of the patients including intracranial tumor location. Therefore, the methylation status of the ELMO gene promoter CpG islands is unlikely to have prognostic value in glioblastoma. Full article

(This article belongs to the Special Issue DNA Methylation)

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18 pages, 824 KiB

Open AccessArticle

A Novel Computational Method for Detecting DNA Methylation Sites with DNA Sequence Information and Physicochemical Properties

by Gaofeng Pan, Limin Jiang, Jijun Tang and Fei Guo

Int. J. Mol. Sci. 2018, 19(2), 511; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020511 - 08 Feb 2018

Cited by 37 | Viewed by 4941

Abstract

DNA methylation is an important biochemical process, and it has a close connection with many types of cancer. Research about DNA methylation can help us to understand the regulation mechanism and epigenetic reprogramming. Therefore, it becomes very important to recognize the methylation sites in the DNA sequence. In the past several decades, many computational methods—especially machine learning methods—have been developed since the high-throughout sequencing technology became widely used in research and industry. In order to accurately identify whether or not a nucleotide residue is methylated under the specific DNA sequence context, we propose a novel method that overcomes the shortcomings of previous methods for predicting methylation sites. We use k-gram, multivariate mutual information, discrete wavelet transform, and pseudo amino acid composition to extract features, and train a sparse Bayesian learning model to do DNA methylation prediction. Five criteria—area under the receiver operating characteristic curve (AUC), Matthew’s correlation coefficient (MCC), accuracy (ACC), sensitivity (SN), and specificity—are used to evaluate the prediction results of our method. On the benchmark dataset, we could reach

0.8632

on AUC,

0.8017

on ACC,

0.5558

on MCC, and

0.7268

on SN. Additionally, the best results on two scBS-seq profiled mouse embryonic stem cells datasets were

0.8896

and

0.9511

by AUC, respectively. When compared with other outstanding methods, our method surpassed them on the accuracy of prediction. The improvement of AUC by our method compared to other methods was at least

0.0399

. For the convenience of other researchers, our code has been uploaded to a file hosting service, and can be downloaded from: https://figshare.com/s/0697b692d802861282d3. Full article

(This article belongs to the Special Issue DNA Methylation)

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22 pages, 909 KiB

Open AccessArticle

Changes in DNA Methylation from Age 18 to Pregnancy in Type 1, 2, and 17 T Helper and Regulatory T-Cells Pathway Genes

by Sabrina Iqbal, Gabrielle A. Lockett, John W. Holloway, S. Hasan Arshad, Hongmei Zhang, Akhilesh Kaushal, Sabarinath R. Tetali, Nandini Mukherjee and Wilfried J. J. Karmaus

Int. J. Mol. Sci. 2018, 19(2), 477; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020477 - 06 Feb 2018

Cited by 9 | Viewed by 4575

Abstract

To succeed, pregnancies need to initiate immune biases towards T helper 2 (Th2) responses, yet little is known about what establishes this bias. Using the Illumina 450 K platform, we explored changes in DNA methylation (DNAm) of Th1, Th2, Th17, and regulatory T cell pathway genes before and during pregnancy. Female participants were recruited at birth (1989), and followed through age 18 years and their pregnancy (2011–2015). Peripheral blood DNAm was measured in 245 girls at 18 years; from among these girls, the DNAm of 54 women was repeatedly measured in the first (weeks 8–21, n = 39) and second (weeks 22–38, n = 35) halves of pregnancy, respectively. M-values (logit-transformed β-values of DNAm) were analyzed: First, with repeated measurement models, cytosine–phosphate–guanine sites (CpGs) of pathway genes in pregnancy and at age 18 (nonpregnant) were compared for changes (p ≤ 0.05). Second, we tested how many of the 348 pathway-related CpGs changed compared to 10 randomly selected subsets of all other CpGs and compared to 10 randomly selected subsets of other CD4+-related CpGs (348 in each subset). Contrasted to the nonpregnant state, 27.7% of Th1-related CpGs changed in the first and 36.1% in the second half of pregnancy. Among the Th2 pathway CpGs, proportions of changes were 35.1% (first) and 33.8% (second half). The methylation changes suggest involvement of both Th1 and Th2 pathway CpGs in the immune bias during pregnancy. Changes in regulatory T cell and Th17 pathways need further exploration. Full article

(This article belongs to the Special Issue DNA Methylation)

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2646 KiB

Open AccessArticle

Inter-Strain Differences in LINE-1 DNA Methylation in the Mouse Hematopoietic System in Response to Exposure to Ionizing Radiation

by Isabelle R. Miousse, Jianhui Chang, Lijian Shao, Rupak Pathak, Étienne Nzabarushimana, Kristy R. Kutanzi, Reid D. Landes, Alan J. Tackett, Martin Hauer-Jensen, Daohong Zhou and Igor Koturbash

Int. J. Mol. Sci. 2017, 18(7), 1430; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18071430 - 04 Jul 2017

Cited by 107 | Viewed by 5079

Abstract

Long Interspersed Nuclear Element 1 (LINE-1) retrotransposons are the major repetitive elements in mammalian genomes. LINE-1s are well-accepted as driving forces of evolution and critical regulators of the expression of genetic information. Alterations in LINE-1 DNA methylation may lead to its aberrant activity and are reported in virtually all human cancers and in experimental carcinogenesis. In this study, we investigated the endogenous DNA methylation status of the 5′ untranslated region (UTR) of LINE-1 elements in the bone marrow hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), and mononuclear cells (MNCs) in radioresistant C57BL/6J and radiosensitive CBA/J mice and in response to ionizing radiation (IR). We demonstrated that basal levels of DNA methylation within the 5′-UTRs of LINE-1 elements did not differ significantly between the two mouse strains and were negatively correlated with the evolutionary age of LINE-1 elements. Meanwhile, the expression of LINE-1 elements was higher in CBA/J mice. At two months after irradiation to 0.1 or 1 Gy of ¹³⁷Cs (dose rate 1.21 Gy/min), significant decreases in LINE-1 DNA methylation in HSCs were observed in prone to radiation-induced carcinogenesis CBA/J, but not C57BL/6J mice. At the same time, no residual DNA damage, increased ROS, or changes in the cell cycle were detected in HSCs of CBA/J mice. These results suggest that epigenetic alterations may potentially serve as driving forces of radiation-induced carcinogenesis; however, future studies are needed to demonstrate the direct link between the LINE-1 DNA hypomethylation and radiation carcinogenesis. Full article

(This article belongs to the Special Issue DNA Methylation)

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Review

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17 pages, 11365 KiB

Open AccessReview

Dynamic DNA Methylation in Plant Growth and Development

by Arthur Bartels, Qiang Han, Pooja Nair, Liam Stacey, Hannah Gaynier, Matthew Mosley, Qi Qing Huang, Jacob K. Pearson, Tzung-Fu Hsieh, Yong-Qiang Charles An and Wenyan Xiao

Int. J. Mol. Sci. 2018, 19(7), 2144; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19072144 - 23 Jul 2018

Cited by 179 | Viewed by 11994

Abstract

DNA methylation is an epigenetic modification required for transposable element (TE) silencing, genome stability, and genomic imprinting. Although DNA methylation has been intensively studied, the dynamic nature of methylation among different species has just begun to be understood. Here we summarize the recent progress in research on the wide variation of DNA methylation in different plants, organs, tissues, and cells; dynamic changes of methylation are also reported during plant growth and development as well as changes in response to environmental stresses. Overall DNA methylation is quite diverse among species, and it occurs in CG, CHG, and CHH (H = A, C, or T) contexts of genes and TEs in angiosperms. Moderately expressed genes are most likely methylated in gene bodies. Methylation levels decrease significantly just upstream of the transcription start site and around transcription termination sites; its levels in the promoter are inversely correlated with the expression of some genes in plants. Methylation can be altered by different environmental stimuli such as pathogens and abiotic stresses. It is likely that methylation existed in the common eukaryotic ancestor before fungi, plants and animals diverged during evolution. In summary, DNA methylation patterns in angiosperms are complex, dynamic, and an integral part of genome diversity after millions of years of evolution. Full article

(This article belongs to the Special Issue DNA Methylation)

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16 pages, 2353 KiB

Open AccessReview

DNA Methyltransferases, DNA Methylation, and Age-Associated Cognitive Function

by Di Cui and Xiangru Xu

Int. J. Mol. Sci. 2018, 19(5), 1315; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051315 - 28 Apr 2018

Cited by 95 | Viewed by 8024

Abstract

Ageing, a leading cause of the decline/deficits in human learning, memory, and cognitive abilities, is a major risk factor for age-associated neurodegenerative disorders such as Alzheimer’s disease. Emerging evidence suggests that epigenetics, an inheritable but reversible biochemical process, plays a crucial role in the pathogenesis of age-related neurological disorders. DNA methylation, the best-known epigenetic mark, has attracted most attention in this regard. DNA methyltransferases (DNMTs) are key enzymes in mediating the DNA methylation process, by which a methyl group is transferred, faithfully or anew, to genomic DNA sequences. Biologically, DNMTs are important for gene imprinting. Accumulating evidence suggests that DNMTs not only play critical roles, including gene imprinting and transcription regulation, in early development stages of the central nervous system (CNS), but also are indispensable in adult learning, memory, and cognition. Therefore, the impact of DNMTs and DNA methylation on age-associated cognitive functions and neurodegenerative diseases has emerged as a pivotal topic in the field. In this review, the effects of each DNMT on CNS development and healthy and pathological ageing are discussed. Full article

(This article belongs to the Special Issue DNA Methylation)

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13 pages, 2999 KiB

Open AccessReview

Defining Driver DNA Methylation Changes in Human Cancer

by Gerd P. Pfeifer

Int. J. Mol. Sci. 2018, 19(4), 1166; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19041166 - 12 Apr 2018

Cited by 219 | Viewed by 15554

Abstract

Human malignant tumors are characterized by pervasive changes in the patterns of DNA methylation. These changes include a globally hypomethylated tumor cell genome and the focal hypermethylation of numerous 5′-cytosine-phosphate-guanine-3′ (CpG) islands, many of them associated with gene promoters. It has been challenging to link specific DNA methylation changes with tumorigenesis in a cause-and-effect relationship. Some evidence suggests that cancer-associated DNA hypomethylation may increase genomic instability. Promoter hypermethylation events can lead to silencing of genes functioning in pathways reflecting hallmarks of cancer, including DNA repair, cell cycle regulation, promotion of apoptosis or control of key tumor-relevant signaling networks. A convincing argument for a tumor-driving role of DNA methylation can be made when the same genes are also frequently mutated in cancer. Many of the most commonly hypermethylated genes encode developmental transcription factors, the methylation of which may lead to permanent gene silencing. Inactivation of such genes will deprive the cells in which the tumor may initiate from the option of undergoing or maintaining lineage differentiation and will lock them into a perpetuated stem cell-like state thus providing an additional window for cell transformation. Full article

(This article belongs to the Special Issue DNA Methylation)

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Open AccessReview

Impact of Natural Compounds on DNA Methylation Levels of the Tumor Suppressor Gene RASSF1A in Cancer

by Reinhard H. Dammann, Antje M. Richter, Adriana P. Jiménez, Michelle Woods, Miriam Küster and Chamindri Witharana

Int. J. Mol. Sci. 2017, 18(10), 2160; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18102160 - 17 Oct 2017

Cited by 36 | Viewed by 6293

Abstract

Epigenetic inactivation of tumor suppressor genes (TSG) is a fundamental event in the pathogenesis of human cancer. This silencing is accomplished by aberrant chromatin modifications including DNA hypermethylation of the gene promoter. One of the most frequently hypermethylated TSG in human cancer is the Ras Association Domain Family 1A (RASSF1A) gene. Aberrant methylation of RASSF1A has been reported in melanoma, sarcoma and carcinoma of different tissues. RASSF1A hypermethylation has been correlated with tumor progression and poor prognosis. Reactivation of epigenetically silenced TSG has been suggested as a therapy in cancer treatment. In particular, natural compounds isolated from herbal extracts have been tested for their capacity to induce RASSF1A in cancer cells, through demethylation. Here, we review the treatment of cancer cells with natural supplements (e.g., methyl donors, vitamins and polyphenols) that have been utilized to revert or prevent the epigenetic silencing of RASSF1A. Moreover, we specify pathways that were involved in RASSF1A reactivation. Several of these compounds (e.g., reseveratol and curcumin) act by inhibiting the activity or expression of DNA methyltransferases and reactive RASSF1A in cancer. Thus natural compounds could serve as important agents in tumor prevention or cancer therapy. However, the exact epigenetic reactivation mechanism is still under investigation. Full article

(This article belongs to the Special Issue DNA Methylation)

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