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Epigenomes, Volume 7, Issue 1 (March 2023) – 8 articles

Cover Story (view full-size image): Abnormal epigenetic regulation is strongly linked to the initiation and progression of breast cancer. The epigenetic changes depend on specific enzymes, including DNA methyltransferases and histone deacetylases. In addition, epigenetic mechanisms are regulated via various signaling pathways, such as 17-beta estradiol (E2) and Wnt signaling, which are promising targets for epigenetic-based therapy in breast cancer patients. However, there are several challenges related to the main strategies of epidrugs with respect to cytotoxicity, resistance, and efficacy. Therefore, in recent epigenetic-targeted therapies, the use of epidrugs in combination with other anti-cancer drugs for tumor remission, reduced resistance to chemotherapy, and fewer side effects has emerged as a promising cancer treatment. View this paper
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28 pages, 9189 KiB  
Article
Epigenome-Wide Changes in the Cell Layers of the Vein Wall When Exposing the Venous Endothelium to Oscillatory Shear Stress
by Mariya A. Smetanina, Valeria A. Korolenya, Alexander E. Kel, Ksenia S. Sevostyanova, Konstantin A. Gavrilov, Andrey I. Shevela and Maxim L. Filipenko
Epigenomes 2023, 7(1), 8; https://doi.org/10.3390/epigenomes7010008 - 20 Mar 2023
Viewed by 2693
Abstract
Epigenomic changes in the venous cells exerted by oscillatory shear stress towards the endothelium may result in consolidation of gene expression alterations upon vein wall remodeling during varicose transformation. We aimed to reveal such epigenome-wide methylation changes. Primary culture cells were obtained from [...] Read more.
Epigenomic changes in the venous cells exerted by oscillatory shear stress towards the endothelium may result in consolidation of gene expression alterations upon vein wall remodeling during varicose transformation. We aimed to reveal such epigenome-wide methylation changes. Primary culture cells were obtained from non-varicose vein segments left after surgery of 3 patients by growing the cells in selective media after magnetic immunosorting. Endothelial cells were either exposed to oscillatory shear stress or left at the static condition. Then, other cell types were treated with preconditioned media from the adjacent layer’s cells. DNA isolated from the harvested cells was subjected to epigenome-wide study using Illumina microarrays followed by data analysis with GenomeStudio (Illumina), Excel (Microsoft), and Genome Enhancer (geneXplain) software packages. Differential (hypo-/hyper-) methylation was revealed for each cell layer’s DNA. The most targetable master regulators controlling the activity of certain transcription factors regulating the genes near the differentially methylated sites appeared to be the following: (1) HGS, PDGFB, and AR for endothelial cells; (2) HGS, CDH2, SPRY2, SMAD2, ZFYVE9, and P2RY1 for smooth muscle cells; and (3) WWOX, F8, IGF2R, NFKB1, RELA, SOCS1, and FXN for fibroblasts. Some of the identified master regulators may serve as promising druggable targets for treating varicose veins in the future. Full article
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17 pages, 1071 KiB  
Review
Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery
by Nando Dulal Das, Hideaki Niwa and Takashi Umehara
Epigenomes 2023, 7(1), 7; https://doi.org/10.3390/epigenomes7010007 - 11 Mar 2023
Cited by 5 | Viewed by 3168
Abstract
The dynamic regulation of histone methylation and demethylation plays an important role in the regulation of gene expression. Aberrant expression of histone lysine demethylases has been implicated in various diseases including intractable cancers, and thus lysine demethylases serve as promising therapeutic targets. Recent [...] Read more.
The dynamic regulation of histone methylation and demethylation plays an important role in the regulation of gene expression. Aberrant expression of histone lysine demethylases has been implicated in various diseases including intractable cancers, and thus lysine demethylases serve as promising therapeutic targets. Recent studies in epigenomics and chemical biology have led to the development of a series of small-molecule demethylase inhibitors that are potent, specific, and have in vivo efficacy. In this review, we highlight emerging small-molecule inhibitors targeting the histone lysine demethylases and their progress toward drug discovery. Full article
(This article belongs to the Special Issue Epidrugs: Toward Understanding and Treating Diverse Diseases)
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16 pages, 995 KiB  
Review
Epigenetic Regulation in Breast Cancer: Insights on Epidrugs
by Ayoung Kim, Kyumin Mo, Hyeonseok Kwon, Soohyun Choe, Misung Park, Woori Kwak and Hyunho Yoon
Epigenomes 2023, 7(1), 6; https://doi.org/10.3390/epigenomes7010006 - 18 Feb 2023
Cited by 10 | Viewed by 4661
Abstract
Breast cancer remains a common cause of cancer-related death in women. Therefore, further studies are necessary for the comprehension of breast cancer and the revolution of breast cancer treatment. Cancer is a heterogeneous disease that results from epigenetic alterations in normal cells. Aberrant [...] Read more.
Breast cancer remains a common cause of cancer-related death in women. Therefore, further studies are necessary for the comprehension of breast cancer and the revolution of breast cancer treatment. Cancer is a heterogeneous disease that results from epigenetic alterations in normal cells. Aberrant epigenetic regulation is strongly associated with the development of breast cancer. Current therapeutic approaches target epigenetic alterations rather than genetic mutations due to their reversibility. The formation and maintenance of epigenetic changes depend on specific enzymes, including DNA methyltransferases and histone deacetylases, which are promising targets for epigenetic-based therapy. Epidrugs target different epigenetic alterations, including DNA methylation, histone acetylation, and histone methylation, which can restore normal cellular memory in cancerous diseases. Epigenetic-targeted therapy using epidrugs has anti-tumor effects on malignancies, including breast cancer. This review focuses on the importance of epigenetic regulation and the clinical implications of epidrugs in breast cancer. Full article
(This article belongs to the Special Issue Epidrugs: Toward Understanding and Treating Diverse Diseases)
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13 pages, 2596 KiB  
Article
SNCA Gene Methylation in Parkinson’s Disease and Multiple System Atrophy
by Ekaterina Yu. Fedotova, Elena V. Iakovenko, Natalia Yu. Abramycheva and Sergey N. Illarioshkin
Epigenomes 2023, 7(1), 5; https://doi.org/10.3390/epigenomes7010005 - 6 Feb 2023
Cited by 5 | Viewed by 2399
Abstract
In recent years, epigenetic mechanisms have been implicated in the development of multifactorial diseases including neurodegenerative disorders. In Parkinson’s disease (PD), as a synucleinopathy, most studies focused on DNA methylation of SNCA gene coding alpha-synuclein but obtained results were rather contradictory. In another [...] Read more.
In recent years, epigenetic mechanisms have been implicated in the development of multifactorial diseases including neurodegenerative disorders. In Parkinson’s disease (PD), as a synucleinopathy, most studies focused on DNA methylation of SNCA gene coding alpha-synuclein but obtained results were rather contradictory. In another neurodegenerative synucleinopathy, multiple system atrophy (MSA), very few studies investigated the epigenetic regulation. This study included patients with PD (n = 82), patients with MSA (n = 24), and a control group (n = 50). In three groups, methylation levels of CpG and non-CpG sites in regulatory regions of the SNCA gene were analyzed. We revealed hypomethylation of CpG sites in the SNCA intron 1 in PD and hypermethylation of predominantly non-CpG sites in the SNCA promoter region in MSA. In PD patients, hypomethylation in the intron 1 was associated with earlier age at the disease onset. In MSA patients, hypermethylation in the promotor was associated with shorter disease duration (before examination). These results showed different patterns of the epigenetic regulation in two synucleinopathies—PD and MSA. Full article
(This article belongs to the Special Issue Non-CpG Methylation)
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17 pages, 551 KiB  
Article
DNA Methylation Is a Potential Biomarker for Cardiometabolic Health in Mexican Children and Adolescents
by Abeer A. Aljahdali, Jaclyn M. Goodrich, Dana C. Dolinoy, Hyungjin M. Kim, Edward A. Ruiz-Narváez, Ana Baylin, Alejandra Cantoral, Libni A. Torres-Olascoaga, Martha M. Téllez-Rojo and Karen E. Peterson
Epigenomes 2023, 7(1), 4; https://doi.org/10.3390/epigenomes7010004 - 3 Feb 2023
Viewed by 2365
Abstract
DNA methylation (DNAm) is a plausible mechanism underlying cardiometabolic abnormalities, but evidence is limited among youth. This analysis included 410 offspring of the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohort followed up to two time points in late childhood/adolescence. [...] Read more.
DNA methylation (DNAm) is a plausible mechanism underlying cardiometabolic abnormalities, but evidence is limited among youth. This analysis included 410 offspring of the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohort followed up to two time points in late childhood/adolescence. At Time 1, DNAm was quantified in blood leukocytes at long interspersed nuclear elements (LINE-1), H19, and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), and at Time 2 in peroxisome proliferator-activated receptor alpha (PPAR-α). At each time point, cardiometabolic risk factors were assessed including lipid profiles, glucose, blood pressure, and anthropometry. Linear mixed effects models were used for LINE-1, H19, and 11β-HSD-2 to account for the repeated-measure outcomes. Linear regression models were conducted for the cross-sectional association between PPAR-α with the outcomes. DNAm at LINE-1 was associated with log glucose at site 1 [β = −0.029, p = 0.0006] and with log high-density lipoprotein cholesterol at site 3 [β = 0.063, p = 0.0072]. 11β-HSD-2 DNAm at site 4 was associated with log glucose (β = −0.018, p = 0.0018). DNAm at LINE-1 and 11β-HSD-2 was associated with few cardiometabolic risk factors among youth in a locus-specific manner. These findings underscore the potential for epigenetic biomarkers to increase our understanding of cardiometabolic risk earlier in life. Full article
(This article belongs to the Special Issue Environmental Epigenomes)
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2 pages, 177 KiB  
Editorial
Acknowledgment to the Reviewers of Epigenomes in 2022
by Epigenomes Editorial Office
Epigenomes 2023, 7(1), 3; https://doi.org/10.3390/epigenomes7010003 - 13 Jan 2023
Viewed by 1342
Abstract
High-quality academic publishing is built on rigorous peer review [...] Full article
11 pages, 1037 KiB  
Brief Report
Sex-Specific miRNA Differences in Liquid Biopsies from Subjects with Solid Tumors and Healthy Controls
by Elena Tomeva, Ulrike D. B. Krammer, Olivier J. Switzeny, Alexander G. Haslberger and Berit Hippe
Epigenomes 2023, 7(1), 2; https://doi.org/10.3390/epigenomes7010002 - 10 Jan 2023
Cited by 6 | Viewed by 3691
Abstract
Dysregulation of epigenetic mechanisms has been recognized to play a crucial role in cancer development, but these mechanisms vary between sexes. Therefore, we focused on sex-specific differences in the context of cancer-based data from a recent study. A total of 12 cell-free DNA [...] Read more.
Dysregulation of epigenetic mechanisms has been recognized to play a crucial role in cancer development, but these mechanisms vary between sexes. Therefore, we focused on sex-specific differences in the context of cancer-based data from a recent study. A total of 12 cell-free DNA methylation targets in CpG-rich promoter regions and 48 miRNAs were analyzed by qPCR in plasma samples from 8 female and 7 male healthy controls as well as 48 female and 80 male subjects with solid tumors of the bladder, brain, colorectal region (CRC), lung, stomach, pancreas, and liver. Due to the small sample size in some groups and/or the non-balanced distribution of men and women, sex-specific differences were evaluated statistically only in healthy subjects, CRC, stomach or pancreas cancer patients, and all cancer subjects combined (n female/male—8/7, 14/14, 8/15, 6/6, 48/80, respectively). Several miRNAs with opposing expressions between the sexes were observed for healthy subjects (miR-17-5p, miR-26b-5p); CRC patients (miR-186-5p, miR-22-3p, miR-22-5p, miR-25-3p, miR-92a-3p, miR-16-5p); stomach cancer patients (miR-133a-3p, miR-22-5p); and all cancer patients combined (miR-126-3p, miR-21-5p, miR-92a-3p, miR-183-5p). Moreover, sex-specific correlations that were dependent on cancer stage were observed in women (miR-27a-3p) and men (miR-17-5p, miR-20a-5p). Our results indicate the complex and distinct role of epigenetic regulation, particularly miRNAs, depending not only on the health status but also on the sex of the patient. The same miRNAs could have diverse effects in different tissues and opposing effects between the biological sexes, which should be considered in biomarker research. Full article
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29 pages, 21798 KiB  
Review
Environmental Adaptation of Genetically Uniform Organisms with the Help of Epigenetic Mechanisms—An Insightful Perspective on Ecoepigenetics
by Günter Vogt
Epigenomes 2023, 7(1), 1; https://doi.org/10.3390/epigenomes7010001 - 26 Dec 2022
Cited by 4 | Viewed by 4343
Abstract
Organisms adapt to different environments by selection of the most suitable phenotypes from the standing genetic variation or by phenotypic plasticity, the ability of single genotypes to produce different phenotypes in different environments. Because of near genetic identity, asexually reproducing populations are particularly [...] Read more.
Organisms adapt to different environments by selection of the most suitable phenotypes from the standing genetic variation or by phenotypic plasticity, the ability of single genotypes to produce different phenotypes in different environments. Because of near genetic identity, asexually reproducing populations are particularly suitable for the investigation of the potential and molecular underpinning of the latter alternative in depth. Recent analyses on the whole-genome scale of differently adapted clonal animals and plants demonstrated that epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNAs are among the molecular pathways supporting phenotypic plasticity and that epigenetic variation is used to stably adapt to different environments. Case studies revealed habitat-specific epigenetic fingerprints that were maintained over subsequent years pointing at the existence of epigenetic ecotypes. Environmentally induced epimutations and corresponding gene expression changes provide an ideal means for fast and directional adaptation to changing or new conditions, because they can synchronously alter phenotypes in many population members. Because microorganisms inclusive of human pathogens also exploit epigenetically mediated phenotypic variation for environmental adaptation, this phenomenon is considered a universal biological principle. The production of different phenotypes from the same DNA sequence in response to environmental cues by epigenetic mechanisms also provides a mechanistic explanation for the “general-purpose genotype hypothesis” and the “genetic paradox of invasions”. Full article
(This article belongs to the Special Issue Environmental Epigenomes)
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