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Epigenomes, Volume 4, Issue 2 (June 2020) – 5 articles

Cover Story (view full-size image): DNA methylation brings balance to the stem force. DNA methylation dynamics orchestrates the normal homeostatic balance between stem cell (SC) self-renewal and differentiation. Alterations in this epigenetic mark in adult stem cells can lead to tumor initiation. The image depicts the example of an early adenomatous lesion (the “dark side”, delineated by intracellular β-catenin translocation, in grey), adjacent to healthy intestinal mucosa (the “light side” on the left). De novo methyltransferase Dnmt3b (red) is expressed in healthy SCs, and its expression becomes predominant in adenomas, reflecting tumor SC accumulation. Aberrant DNA methylation patterns may be targeted to preserve the homeostatic balance in adult SCs. View this paper
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10 pages, 2440 KiB  
Article
Exploring DNA Methylation Diversity in the Honey Bee Brain by Ultra-Deep Amplicon Sequencing
by Robert Kucharski and Ryszard Maleszka
Epigenomes 2020, 4(2), 10; https://doi.org/10.3390/epigenomes4020010 - 25 Jun 2020
Cited by 11 | Viewed by 3821
Abstract
Understanding methylation dynamics in organs or tissues containing many different cell types is a challenging task that cannot be efficiently addressed by the low-depth bisulphite sequencing of DNA extracted from such sources. Here we explored the feasibility of ultra-deep bisulphite sequencing of long [...] Read more.
Understanding methylation dynamics in organs or tissues containing many different cell types is a challenging task that cannot be efficiently addressed by the low-depth bisulphite sequencing of DNA extracted from such sources. Here we explored the feasibility of ultra-deep bisulphite sequencing of long amplicons to reveal the brain methylation patterns in three selected honey bee genes analysed across five distinct conditions on the Illumina MiSeq platform. By combing 15 libraries in one run we achieved a very high sequencing depth of 240,000–340,000 reads per amplicon, suggesting that most of the cell types in the honey bee brain, containing approximately 1 million neurons, are represented in this dataset. We found a small number of gene-specific patterns for each condition in individuals of different ages and performing distinct tasks with 80–90% of those were represented by no more than a dozen patterns. One possibility is that such a small number of frequent patterns is the result of differentially methylated epialleles, whereas the rare and less frequent patterns reflect activity-dependent modifications. The condition-specific methylation differences within each gene appear to be position-dependent with some CpGs showing significant changes and others remaining stable in a methylated or non-methylated state. Interestingly, no significant loss of methylation was detected in very old individuals. Our findings imply that these diverse patterns represent a special challenge in the analyses of DNA methylation in complex tissues and organs that cannot be investigated by low-depth genome-wide bisulphite sequencing. We conclude that ultra-deep sequencing of gene-specific amplicons combined with genotyping of differentially methylated epialleles is an effective way to facilitate more advanced neuro-epigenomic studies in honey bees and other insects. Full article
(This article belongs to the Special Issue Epigenetics of the Nervous System 2.0)
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8 pages, 843 KiB  
Article
Promoter and Terminator Optimization for DNA Methylation Targeting in Arabidopsis
by Jason Gardiner, Jenny M. Zhao, Kendall Chaffin and Steven E. Jacobsen
Epigenomes 2020, 4(2), 9; https://doi.org/10.3390/epigenomes4020009 - 12 Jun 2020
Cited by 4 | Viewed by 5007
Abstract
DNA methylation is an important epigenetic mark involved in gene regulation and silencing of transposable elements. The presence or absence of DNA methylation at specific sites can influence nearby gene expression and cause phenotypic changes that remain stable over generations. Recently, development of [...] Read more.
DNA methylation is an important epigenetic mark involved in gene regulation and silencing of transposable elements. The presence or absence of DNA methylation at specific sites can influence nearby gene expression and cause phenotypic changes that remain stable over generations. Recently, development of new technologies has enabled the targeted addition or removal of DNA methylation at specific sites of the genome. Of these new technologies, the targeting of the catalytic domain of Nicotiana tabacum DOMAINS REARRANGED METHYLTRANSFERASE 2 (ntDRM2cd) offers a promising tool for the addition of DNA methylation as it can directly methylate DNA. However, the methylation targeting efficiency of constructs using ntDRM2cd thus far has been relatively low. Previous studies have shown that the use of different promoters or terminators can greatly improve genome-editing efficiencies. In this study, we systematically survey a variety of promoter and terminator combinations to identify optimal combinations to use when targeting the addition of DNA methylation in Arabidopsis thaliana. Full article
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17 pages, 2929 KiB  
Review
The Epigenetic Progenitor Origin of Cancer Reassessed: DNA Methylation Brings Balance to the Stem Force
by Marco Bruschi
Epigenomes 2020, 4(2), 8; https://doi.org/10.3390/epigenomes4020008 - 28 May 2020
Cited by 5 | Viewed by 4022
Abstract
Cancer initiation and progression toward malignant stages occur as the results of accumulating genetic alterations and epigenetic dysregulation. During the last decade, the development of next generation sequencing (NGS) technologies and the increasing pan-genomic knowledge have revolutionized how we consider the evolving epigenetic [...] Read more.
Cancer initiation and progression toward malignant stages occur as the results of accumulating genetic alterations and epigenetic dysregulation. During the last decade, the development of next generation sequencing (NGS) technologies and the increasing pan-genomic knowledge have revolutionized how we consider the evolving epigenetic landscapes during homeostasis and tumor progression. DNA methylation represents the best studied mark and is considered as a common mechanism of epigenetic regulation in normal homeostasis and cancer. A remarkable amount of work has recently started clarifying the central role played by DNA methylation dynamics on the maintenance of cell identity and on cell fate decisions during the different steps of normal development and tumor evolution. Importantly, a growing number of studies show that DNA methylation is key in the maintenance of adult stemness and in orchestrating commitment in multiple ways. Perturbations of the normal DNA methylation patterns impair the homeostatic balance and can lead to tumor initiation. Therefore, DNA methylation represents an interesting therapeutic target to recover homeostasis in tumor stem cells. Full article
(This article belongs to the Special Issue Epigenetics in Stem Cells and Their Derivatives)
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15 pages, 2012 KiB  
Review
Anticodon Wobble Uridine Modification by Elongator at the Crossroad of Cell Signaling, Differentiation, and Diseases
by Damien Hermand
Epigenomes 2020, 4(2), 7; https://doi.org/10.3390/epigenomes4020007 - 12 May 2020
Cited by 8 | Viewed by 4239
Abstract
First identified 20 years ago as an RNA polymerase II-associated putative histone acetyltransferase, the conserved Elongator complex has since been recognized as the central player of a complex, regulated, and biologically relevant epitranscriptomic pathway targeting the wobble uridine of some tRNAs. Numerous studies [...] Read more.
First identified 20 years ago as an RNA polymerase II-associated putative histone acetyltransferase, the conserved Elongator complex has since been recognized as the central player of a complex, regulated, and biologically relevant epitranscriptomic pathway targeting the wobble uridine of some tRNAs. Numerous studies have contributed to three emerging concepts resulting from anticodon modification by Elongator: the codon-specific control of translation, the ability of reprogramming translation in various physiological or pathological contexts, and the maintenance of proteome integrity by counteracting protein aggregation. These three aspects of tRNA modification by Elongator constitute a new layer of regulation that fundamentally contributes to gene expression and are now recognized as being critically involved in various human diseases. Full article
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23 pages, 2100 KiB  
Review
An Epigenetics-Based Hypothesis of Autoantigen Development in Systemic Lupus Erythematosus
by Wesley Brooks
Epigenomes 2020, 4(2), 6; https://doi.org/10.3390/epigenomes4020006 - 23 Apr 2020
Cited by 6 | Viewed by 4007
Abstract
Currently, we have a limited understanding of mechanisms leading to systemic lupus erythematosus, but we know that genetics, environmental factors, and epigenetics contribute to the disease. One common aspect of the various environmental triggers is that they can cause cellular stress. When extraordinary [...] Read more.
Currently, we have a limited understanding of mechanisms leading to systemic lupus erythematosus, but we know that genetics, environmental factors, and epigenetics contribute to the disease. One common aspect of the various environmental triggers is that they can cause cellular stress. When extraordinary stress occurs, such as viral activation, a cell’s response can include increased nucleolar volume and activity to produce more machinery (e.g., ribosomes) to help the cell recover. However, nucleolar expansion can disrupt the epigenetic control in neighboring heterochromatin that comprises the nucleolar shell. This disruption can open underlying vulnerabilities that provoke an autoimmune reaction. Here, we review the “X chromosome-nucleolus nexus” hypothesis, which explains how nucleolar stress can disrupt epigenetically silenced chromatin, especially the neighboring inactive X chromosome (aka the nucleolar satellite). Chromatin disruption can lead to the expression of sequestered DNA, such as Alu elements and fully functional LINE-1 reverse transcriptase genes. In addition, Alu transcripts can disrupt the nucleolar structural integrity, leading to nucleolar disintegration. Such disintegration can leave nucleolar components and products in autoantigenic forms, such as abnormal conformations or incomplete macromolecular assemblies. Recent research on DNA sensing pathways can now be incorporated into the hypothesis to provide further details explaining how autoantibodies to endogenous nucleic acids arise. Full article
(This article belongs to the Special Issue Complex Disease Epigenetics)
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