Epigenomes

16 pages, 1855 KiB

Open AccessArticle

DNA Imprinting and Differentially Expressed Genes in Longissimus thoracis Muscle of Bos indicus Submitted to Early Weaning Management

by Gustavo Tinoco, Gustavo Russo, Rogério Curi, Marcelo Vicari, Paloma Melo, Isabella Souza, Juliana Torrecilhas, Philipe Moriel, Welder Baldassini, Luis Chardulo, Otávio Neto and Guilherme Pereira

Epigenomes 2024, 8(4), 45; https://doi.org/10.3390/epigenomes8040045 - 4 Dec 2024

Abstract

Background/Objectives: Early weaning management followed by energy supplementation can lead to metabolic alterations in the calf that exert long-term effects on the animal’s health and performance. It is believed that the main molecular basis underlying these metabolic adaptations are epigenetic mechanisms that regulate, [...] Read more.

Background/Objectives: Early weaning management followed by energy supplementation can lead to metabolic alterations in the calf that exert long-term effects on the animal’s health and performance. It is believed that the main molecular basis underlying these metabolic adaptations are epigenetic mechanisms that regulate, activate, or silence genes at different stages of development and/or in response to different environmental stimuli. However, little is known about postnatal metabolic programming in Bos indicus. Therefore, this study aimed to compare the DNA methylation profile of Nellore animals submitted to conventional and early weaning and to correlate the findings with genes differentially expressed in the Longissimus thoracis skeletal muscle of Bos indicus cattle. Methods: For this, we used Reduced Representation Bisulfite Sequencing (RRBS) and RNA-Sequencing techniques to prospect differentially methylated genes (DMGs). Results: A total of 481 differentially methylated regions were identified, with 52% (250) being hypermethylated and 48% (231) hypomethylated. Functional enrichment analysis of 53 differentially methylated and differentially expressed genes was performed. The main enriched terms and pathways were associated with 3′-5′-cyclic adenosine monophosphate (cAMP) signaling, which presents the upregulated adenylate cyclase 3 (ADCY3) gene and significatively hypomethylated in the promoter region. Alterations in cAMP signaling are involved in numerous processes, many of them related to lipid metabolism. The relative differential expression of key genes of this pathway demonstrates the relationship between cAMP signaling and de novo lipogenesis. Conclusions: These findings suggest an important role of postnatal metabolic programming through DNA methylation mechanisms in determining fat deposition in beef. Full article

(This article belongs to the Collection Feature Papers in Epigenomes)

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18 pages, 1760 KiB

Open AccessArticle

Environmental Factor Index (EFI): A Novel Approach to Measure the Strength of Environmental Influence on DNA Methylation in Identical Twins

by Yoichi Takenaka, Osaka Twin Research Group and Mikio Watanabe

Epigenomes 2024, 8(4), 44; https://doi.org/10.3390/epigenomes8040044 - 21 Nov 2024

Abstract

Background/Objectives: The dynamic interaction between genomic DNA, epigenetic modifications, and phenotypic traits was examined in identical twins. Environmental perturbations can induce epigenetic changes in DNA methylation, influencing gene expression and phenotypes. Although DNA methylation mediates gene-environment correlations, the quantitative effects of external factors [...] Read more.

Background/Objectives: The dynamic interaction between genomic DNA, epigenetic modifications, and phenotypic traits was examined in identical twins. Environmental perturbations can induce epigenetic changes in DNA methylation, influencing gene expression and phenotypes. Although DNA methylation mediates gene-environment correlations, the quantitative effects of external factors on DNA methylation remain underexplored. This study aimed to quantify these effects using a novel approach. Methods: A cohort study was conducted on healthy monozygotic twins to evaluate the influence of environmental stimuli on DNA methylation. We developed the Environmental Factor Index (EFI) to identify methylation sites showing statistically significant changes in response to environmental stimuli. We analyzed the identified sites for associations with disorders, DNA methylation markers, and CpG islands. Results: The EFI identified methylation sites that exhibited significant associations with genes linked to various disorders, particularly cancer. These sites were overrepresented on CpG islands compared to other genomic features, highlighting their regulatory importance. Conclusions: The EFI is a valuable tool for understanding the molecular mechanisms underlying disease pathogenesis. It provides insights into the development of preventive and therapeutic strategies and offers a new perspective on the role of environmental factors in epigenetic regulation. Full article

(This article belongs to the Collection Feature Papers in Epigenomes)

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Figure 1
Difference between the EFI and coefficient correlation of DNA methylation values and age: (a) distribution of correlation coefficients between methylation values and chronological age for each DNA methylation site; (b) scatter plot of EFI and the correlation coefficient. Each point represents a methylation site, plotting its EFI value on the y-axis against its corresponding correlation coefficient on the x-axis. Full article ">Figure 2
Statistics on EFI. (a) Scatter chart of SDs for young twins (<53 years-old) and elderly twins (≥53 years-old). The x- and y-axes correspond to the denominator and numerator of the EFI, respectively. Each dot represents a methylation site. (b) p-values of Levene’s test and q-values representing the probabilities adjusted for multiple testing correction. (c) Scatter chart of EFI and FDR from Levene’s test between young and elderly twins. Each dot represents a methylation site. Both axes are logarithmic. (d) Histogram of EFI. Both axes are logarithmic. Full article ">Figure 3
Statistics related to the subjects and data collected for the DNA methylation probes. (a) Age distribution of the twin pairs. The x-axis represents the age, and the y-axis represents the number of pairs. (b) Similar histograms showing the age distribution of the twin pairs differentiated by sex. The axes are the same as in (a). (c) Histogram illustrating how many valid observations were collected for each DNA methylation probe. The x-axis shows the number of valid observations, and the y-axis represents the number of probes. (d) Representative ages of the subjects (the left table) and the number of valid subjects for each probe (the right table). The values in the right table represent basic statistics of DNA methylation probes when sorted in ascending order by the number of valid subjects. Full article ">

10 pages, 1876 KiB

Open AccessArticle

Age-Dependent DNA Methylation Variability on the X-Chromosome in Male and Female Twins

by Qihua Tan, Hikmat Alo, Marianne Nygaard, Mette Sørensen, Alisa Saleh, Jonas Mengel-From and Kaare Christensen

Epigenomes 2024, 8(4), 43; https://doi.org/10.3390/epigenomes8040043 - 18 Nov 2024

Abstract

We aimed to explore the age-dependent epigenetic variability on the X-chromosome with consideration of X-chromosome inactivation by applying a sex-stratified regression analysis to DNA methylation array data on X-linked CpGs in aging identical twins. We found 13 X-linked CpGs showing age-related significant increase [...] Read more.

We aimed to explore the age-dependent epigenetic variability on the X-chromosome with consideration of X-chromosome inactivation by applying a sex-stratified regression analysis to DNA methylation array data on X-linked CpGs in aging identical twins. We found 13 X-linked CpGs showing age-related significant increase in variability in males (FDR < 0.05) but none in females. In females, we found a significantly higher proportion of CpGs showing increased variability with age among nominally significant (p < 0.05) CpGs under inactivation, but not among CpGs escaping inactivation. Survival analysis showed a slight trend of correlation by directional change in the variable CpGs with mortality in males. Compared with females, the male X-chromosome can be more vulnerable to epigenetic instability during aging. Full article

(This article belongs to the Special Issue X-Chromosome Inactivation)

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Volcano plot of association test on DNAm variability in male (a) and female (b) twins, with negative log of the p value (base 10) for each CpG site on the Y-axis, and age-dependent change in DNAm variability (as regression coefficient for age) on the X-axis. The red dots represent CpGs showing significant age-related intra-pair methylation discordance with FDR < 0.05. Full article ">Figure 2
A scatter plot showing the estimated effect size of age (regression coefficient) on DNAm variability in males on the Y-axis plotted against that in females on the X-axis. The red and green dots represent CpGs detected as under and escaping XCI in females, respectively. The diamond represents significantly variable CpGs in males. Full article ">Figure 3
Scatter plots demonstrating the relationship between age-related DNAm variability (Y-axis, regression coefficient for age) and mortality (X-axis, Cox regression coefficient) in males (left) and females (right). The purple diamonds in the left panel represent CpGs significant for DNAm variability in males. The blue triangles in the left panel show CpGs significant for risk of death in males. The large triangles in the right panel are the 6 CpGs significant for mortality in females. CpGs under and escaping XCI in females are coloured red and green respectively in the right panel. The rest of X-linked CpGs are coloured black. Full article ">Figure 4
Scatter plot showing the Cox regression coefficient (the effect size on mortality) of each varying CpG (Y-axis) plotted against its mean of intra-pair DNAm difference (X-axis, long-lived twin (L) minus short-lived twin (S)) with CpGs having L−S > 0 coloured red and CpGs having L−S < 0 coloured green. The bigger the size of the dots, the more statistically significant in the survival analysis. Full article ">

8 pages, 694 KiB

Open AccessOpinion

Histone Modification Pathways Suppressing Cryptic Transcription

by Hong-Yeoul Ryu

Epigenomes 2024, 8(4), 42; https://doi.org/10.3390/epigenomes8040042 - 12 Nov 2024

Abstract

Cryptic transcription refers to the unintended expression of non-canonical sites within the genome, producing aberrant RNA and proteins that may disrupt cellular functions. In this opinion piece, I will explore the role of histone modifications in modulating cryptic transcription and its implications for [...] Read more.

Cryptic transcription refers to the unintended expression of non-canonical sites within the genome, producing aberrant RNA and proteins that may disrupt cellular functions. In this opinion piece, I will explore the role of histone modifications in modulating cryptic transcription and its implications for gene expression and cellular integrity, particularly with a focus on H3K36 and H3K4 methylation marks. H3K36 tri-methylation plays a crucial role in maintaining chromatin integrity by facilitating the recruitment of the Rpd3S histone deacetylase (HDAC) complex, which helps restore closed chromatin states following transcription and prevents cryptic initiation within gene bodies. In parallel, crosstalk between H3K4 di-methylation and histone ubiquitylation and sumoylation is critical for recruiting the Set3 HDAC complex, which maintains low histone acetylation levels in gene bodies and further suppresses cryptic transcription. Therefore, by elucidating these regulatory mechanisms, this opinion highlights the intricate interplay of histone modifications in preserving transcriptional fidelity and suggests potential pathways for future research to develop novel therapies for age-related disorders and other diseases associated with dysregulated gene expression. Full article

(This article belongs to the Special Issue Histone Variants)

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12 pages, 883 KiB

Open AccessReview

Epigenetic Landscape of DNA Methylation in Pancreatic Ductal Adenocarcinoma

by Peiyi Liu, Juliette Jacques and Chang-Il Hwang

Epigenomes 2024, 8(4), 41; https://doi.org/10.3390/epigenomes8040041 - 3 Nov 2024

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by its aggressive progression and dismal prognosis. Advances in epigenetic profiling, specifically DNA methylation analysis, have significantly deepened our understanding of PDAC pathogenesis. This review synthesizes findings from recent genome-wide DNA [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by its aggressive progression and dismal prognosis. Advances in epigenetic profiling, specifically DNA methylation analysis, have significantly deepened our understanding of PDAC pathogenesis. This review synthesizes findings from recent genome-wide DNA methylation studies, which have delineated a complex DNA methylation landscape differentiating between normal and cancerous pancreatic tissues, as well as across various stages and molecular subtypes of PDAC. These studies identified specific differentially methylated regions (DMRs) that not only enhance our grasp of the epigenetic drivers of PDAC but also offer potential biomarkers for early diagnosis and prognosis, enabling the customization of therapeutic approaches. The review further explores how DNA methylation profiling could facilitate the development of subtype-tailored therapies, potentially improving treatment outcomes based on precise molecular characterizations. Overall, leveraging DNA methylation alterations as functional biomarkers holds promise for advancing our understanding of disease progression and refining PDAC management strategies, which could lead to improved patient outcomes and a deeper comprehension of the disease’s underlying biological mechanisms. Full article

(This article belongs to the Special Issue New Insights into Epigenetic Regulation in Cancer)

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16 pages, 3119 KiB

Open AccessArticle

Transcription Factors Are Involved in Wizened Bud Occurrence During the Growing Season in the Pyrus pyrifolia Cultivar ‘Sucui 1’

by Hui Li, Jialiang Kan, Chunxiao Liu, Qingsong Yang, Jing Lin and Xiaogang Li

Epigenomes 2024, 8(4), 40; https://doi.org/10.3390/epigenomes8040040 - 25 Oct 2024

Abstract

Background: Flowers are important plant organs, and their development is correlated with yield in woody fruit trees. For Pyrus pyrifolia cultivar ‘Sucui 1’, the research on how DNA methylation accurately regulates the expression of TFs and affects the specific regulatory mechanism of flower [...] Read more.

Background: Flowers are important plant organs, and their development is correlated with yield in woody fruit trees. For Pyrus pyrifolia cultivar ‘Sucui 1’, the research on how DNA methylation accurately regulates the expression of TFs and affects the specific regulatory mechanism of flower bud wizening will help reduce wizened buds. Methods: Here, the DNA methylomes and transcriptomes of two types of flower buds from the Pyrus pyrifolia cultivar ‘Sucui 1’ were compared. Results: 320 differentially expressed transcription factors (TFs), in 43 families, were obtained from the wizened bud transcriptome versus the normal bud transcriptome. Most were members of the AP2/ERF, bHLH, C2H2, CO-like, MADS, MYB, and WRKY families, which are involved in flower development. As a whole, the methylation level of TFs in the ‘Sucui 1’ genome increased once flower bud wizening occurred. A cytosine methylation analysis revealed that the methylation levels of the same gene regions in TFs from two kinds of buds were similar. However, differentially methylated regions were found in gene promoter sequences. The combined whole-genome bisulfite sequencing and RNA-Seq analyses revealed 162 TF genes (including 164 differentially methylated regions) with both differential expression and methylation differences between the two flower bud types. Among them, 126 were classified as ^mCHH-type methylation genes. Furthermore, the transcriptional down regulation of PpbHLH40, PpERF4, PpERF061, PpLHW, PpMADS6, PpZF-HD11, and PpZFP90 was accompanied by increased DNA methylation. However, PpbHLH130, PpERF011, and PpMYB308 displayed the opposite trend. The expression changes for these TFs were negatively correlated with their methylation states. Conclusions: Overall, our results offer initial experimental evidence of a correlation between DNA methylation and TF transcription in P. pyrifolia in response to bud wizening. This enriched our understanding of epigenetic modulations in woody trees during flower development. Full article

(This article belongs to the Collection Epigenetic Control in Plants)

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19 pages, 11563 KiB

Open AccessArticle

Epigenome Mapping in Quiescent Cells Reveals a Key Role for H3K4me3 in Regulation of RNA Polymerase II Activity

by Shengyuan Zeng and Karl Ekwall

Epigenomes 2024, 8(4), 39; https://doi.org/10.3390/epigenomes8040039 - 22 Oct 2024

Abstract

(1) Background: Quiescent cells are those that have stopped dividing and show strongly reduced levels of gene expression during dormancy. In response to appropriate signals, the cells can wake up and start growing again. Many histone modifications are regulated in quiescence, but their [...] Read more.

(1) Background: Quiescent cells are those that have stopped dividing and show strongly reduced levels of gene expression during dormancy. In response to appropriate signals, the cells can wake up and start growing again. Many histone modifications are regulated in quiescence, but their exact functions remain to be determined. (2) Methods: Here, we map the different histone modifications, H3K4me3, H3K9ac, H3K9me2, and H3K9me3, and the histone variant H2A.Z, comparing vegetative and quiescent fission yeast (S. pombe) cells. We also map histone H3 as a control and RNA polymerase II (phosphorylated at S2 and S5) to enable comparisons of their occupancies within genes. We use ChIP-seq methodology and several different bioinformatics tools. (3) Results: The histone modification mapping data show that H3K4me3 changes stand out as being the most significant. Changes in occupancy of histone variant H2A.Z were also significant, consistent with earlier studies. Regarding gene expression changes in quiescence, we found that changes in mRNA levels were associated with changes in occupancy of RNA polymerase II (S2 and S5). Analysis of quiescence genes showed that increased H3K4me3 levels and RNA polymerase II occupancy were super-significant in a small set of core quiescence genes that are continuously upregulated during dormancy. We demonstrate that several of these genes were require Set1C/COMPASS activity for their strong induction during quiescence. (4) Conclusions: Our results imply that regulation of gene expression in quiescent cells involves epigenome changes with a key role for H3K4me3 in regulation of RNA polymerase II activity, and that different gene activation mechanisms control early and core quiescence genes. Thus, our data give further insights into important epigenome changes in quiescence using fission yeast as an experimental model. Full article

(This article belongs to the Special Issue Histone Variants)

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18 pages, 4934 KiB

Open AccessArticle

Associations between Circulating Biomarkers of One-Carbon Metabolism and Mitochondrial D-Loop Region Methylation Levels

by Andrea Stoccoro, Martina Lari, Lucia Migliore and Fabio Coppedè

Epigenomes 2024, 8(4), 38; https://doi.org/10.3390/epigenomes8040038 - 9 Oct 2024

Cited by 1

Abstract

Background/Objectives: One-carbon metabolism is a critical pathway for epigenetic mechanisms. Circulating biomarkers of one-carbon metabolism have been associated with changes in nuclear DNA methylation levels in individuals affected by age-related diseases. More and more studies are showing that even mitochondrial DNA (mtDNA) could [...] Read more.

Background/Objectives: One-carbon metabolism is a critical pathway for epigenetic mechanisms. Circulating biomarkers of one-carbon metabolism have been associated with changes in nuclear DNA methylation levels in individuals affected by age-related diseases. More and more studies are showing that even mitochondrial DNA (mtDNA) could be methylated. In particular, methylation of the mitochondrial displacement (D-loop) region modulates the gene expression and replication of mtDNA and, when altered, can contribute to the development of human illnesses. However, no study until now has demonstrated an association between circulating biomarkers of one-carbon metabolism and D-loop methylation levels. Methods: In the study presented herein, we searched for associations between circulating one-carbon metabolism biomarkers, including folate, homocysteine, and vitamin B12, and the methylation levels of the D-loop region in DNA obtained from the peripheral blood of 94 elderly voluntary subjects. Results: We observed a positive correlation between D-loop methylation and vitamin B12 (r = 0.21; p = 0.03), while no significant correlation was observed with folate (r = 0.02; p = 0.80) or homocysteine levels (r = 0.02; p = 0.82). Moreover, D-loop methylation was increased in individuals with high vitamin B12 levels compared to those with normal vitamin B12 levels (p = 0.04). Conclusions: This is the first study suggesting an association between vitamin B12 circulating levels and mtDNA methylation in human subjects. Given the potential implications of altered one-carbon metabolism and mitochondrial epigenetics in human diseases, a deeper understanding of their interaction could inspire novel interventions with beneficial effects for human health. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of the 30th Anniversary of the Epigenetics Society)

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Figure 1
Schematic overview of one-carbon metabolism, adapted from [<a href="#B12-epigenomes-08-00038" class="html-bibr">12</a>]. Main metabolites (in rectangles), enzymes (in circles), and cofactors (in hexagons) are reported. In red are the one-carbon metabolism biomarkers analyzed in the current study. Abbreviations: 5-mTHF, 5-methyltetrahydrofolate; 5-10-methylene THF, 5,10-Methylenetetrahydrofolate; AHCY, S-Adenosylhomocysteine hydrolase; ATP, adenosine triphosphate; B6, vitamin B6; CBS, Cystathionine β-synthase; DNMTs, DNA methyltransferases; DHF, dihydrofolate; dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate; GSH, glutathione; MAT, methionine adenosyltransferase; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase reductase; TYMS, thymidilate synthase. Metabolites: 5-mTHF, 5-methyltetrahydrofolate; DHF, dihydrofolate; THF, tetrahydrofolate; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; Vit. B12, vitamin B12. Full article ">Figure 2
Mitochondrial D-loop methylation levels in females and males. The p-value was obtained with the Student-t test. Full article ">Figure 3
Correlation between D-loop methylation levels and age at sampling. The correlation was analyzed using Pearson’s correlation coefficient. Full article ">Figure 4
Folate (A), homocysteine (B), and vitamin B12 (C) in females and males. The p-value was obtained with the Student-t test. Full article ">Figure 5
Correlation between folate (A), homocysteine (B), and vitamin B12 (C) circulating levels and age at sampling. The correlations were analyzed using Pearson’s correlation coefficient. Full article ">Figure 6
Correlations among D-loop methylation and folate (A), homocysteine (B), and vitamin B12 (C) circulating levels. The correlation was analyzed using Pearson’s correlation coefficient. Full article ">Figure 7
D-loop methylation levels in individuals below and within reference values (RV) of folate (A), within and above the RV of homocysteine (B), and in individuals below, within, and above the RV of vitamin B12 (C). p-value obtained with ANCOVA including age as the covariate. Full article ">Figure 8
Comparison of folate (A), homocysteine (B), and vitamin B12 (C) circulating levels between samples with an unmethylated D-loop and those with a methylated D-loop. p-value obtained with ANCOVA including age and sex as covariates. Full article ">

13 pages, 534 KiB

Open AccessArticle

Examining the Utility of the Mammalian Methylation Array for Pan-Mammalian Analysis of Monozygotic Twinning

by Jenny van Dongen, Charles E. Breeze and Twinning Genetics Consortium

Epigenomes 2024, 8(4), 37; https://doi.org/10.3390/epigenomes8040037 - 6 Oct 2024

Abstract

Background/Objectives: Human identical twins are born at a rate of 3–4 per 1000 live births. Many other mammals also occasionally produce monozygotic twins, referred to as sporadic polyembryony. The underlying mechanisms are unknown. Through epigenome-wide association studies (EWAS), we identified a robust DNA [...] Read more.

Background/Objectives: Human identical twins are born at a rate of 3–4 per 1000 live births. Many other mammals also occasionally produce monozygotic twins, referred to as sporadic polyembryony. The underlying mechanisms are unknown. Through epigenome-wide association studies (EWAS), we identified a robust DNA methylation signature in somatic tissues from human monozygotic (MZ) twins, comprising 834 differentially methylated positions (MZ-DMPs). The results point to a connection between monozygotic twinning and early genome programming and enable new angles to study monozygotic twinning. Methods: The mammalian methylation array (MMA) measures 38,608 CpGs focusing on regions that are well-conserved across many mammalian species, allowing for pan-mammalian comparative epigenomic studies. Here, we successfully map human MZ-DMPs to probes of the mammalian methylation array across 157 mammalian genomes. Results: As expected, based on the modest probe overlap between Illumina 450k/EPIC and mammalian methylation array probes, only a subset of MZ-DMPs reside in conserved regions covered by the mammalian methylation array. These include probes mapping to NPAS3, KLHL35, CASZ1, and ATP2B2. Re-analysis restricting the original EWAS in humans to conserved MMA regions yielded additional MZ-DMPs, suggesting that more loci may be detected by application of the mammalian array to monozygotic twins. Conclusions: In conclusion, the mammalian methylation array may prove to be a promising platform to study whether a shared DNA methylation signature of sporadic polyembryony exists across diverse mammalian species. This may potentially point to shared underlying mechanisms. Full article

(This article belongs to the Collection Feature Papers in Epigenomes)

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15 pages, 1022 KiB

Open AccessReview

PHF8/KDM7B: A Versatile Histone Demethylase and Epigenetic Modifier in Nervous System Disease and Cancers

by Tingyu Fan, Jianlian Xie, Guo Huang, Lili Li, Xi Zeng and Qian Tao

Epigenomes 2024, 8(3), 36; https://doi.org/10.3390/epigenomes8030036 - 15 Sep 2024

Abstract

Many human diseases, such as malignant tumors and neurological diseases, have a complex pathophysiological etiology, often accompanied by aberrant epigenetic changes including various histone modifications. Plant homologous domain finger protein 8 (PHF8), also known as lysine-specific demethylase 7B (KDM7B), is a critical histone [...] Read more.

Many human diseases, such as malignant tumors and neurological diseases, have a complex pathophysiological etiology, often accompanied by aberrant epigenetic changes including various histone modifications. Plant homologous domain finger protein 8 (PHF8), also known as lysine-specific demethylase 7B (KDM7B), is a critical histone lysine demethylase (KDM) playing an important role in epigenetic modification. Characterized by the zinc finger plant homology domain (PHD) and the Jumonji C (JmjC) domain, PHF8 preferentially binds to H3K4me3 and erases repressive methyl marks, including H3K9me1/2, H3K27me1, and H4K20me1. PHF8 is indispensable for developmental processes and the loss of PHF8 enzyme activity is linked to neurodevelopmental disorders. Moreover, increasing evidence shows that PHF8 is highly expressed in multiple tumors as an oncogenic factor. These findings indicate that studying the role of PHF8 will facilitate the development of novel therapeutic agents by the manipulation of PHF8 demethylation activity. Herein, we summarize the current knowledge of PHF8 about its structure and demethylation activity and its involvement in development and human diseases, with an emphasis on nervous system disorders and cancer. This review will update our understanding of PHF8 and promote the clinical transformation of its predictive and therapeutic value. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of the 30th Anniversary of the Epigenetics Society)

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17 pages, 984 KiB

Open AccessReview

Retrotransposons and Diabetes Mellitus

by Andromachi Katsanou, Charilaos Kostoulas, Evangelos Liberopoulos, Agathocles Tsatsoulis, Ioannis Georgiou and Stelios Tigas

Epigenomes 2024, 8(3), 35; https://doi.org/10.3390/epigenomes8030035 - 6 Sep 2024

Abstract

Retrotransposons are invasive genetic elements, which replicate by copying and pasting themselves throughout the genome in a process called retrotransposition. The most abundant retrotransposons by number in the human genome are Alu and LINE-1 elements, which comprise approximately 40% of the human genome. [...] Read more.

Retrotransposons are invasive genetic elements, which replicate by copying and pasting themselves throughout the genome in a process called retrotransposition. The most abundant retrotransposons by number in the human genome are Alu and LINE-1 elements, which comprise approximately 40% of the human genome. The ability of retrotransposons to expand and colonize eukaryotic genomes has rendered them evolutionarily successful and is responsible for creating genetic alterations leading to significant impacts on their hosts. Previous research suggested that hypomethylation of Alu and LINE-1 elements is associated with global hypomethylation and genomic instability in several types of cancer and diseases, such as neurodegenerative diseases, obesity, osteoporosis, and diabetes mellitus (DM). With the advancement of sequencing technologies and computational tools, the study of the retrotransposon’s association with physiology and diseases is becoming a hot topic among researchers. Quantifying Alu and LINE-1 methylation is thought to serve as a surrogate measurement of global DNA methylation level. Although Alu and LINE-1 hypomethylation appears to serve as a cellular senescence biomarker promoting genomic instability, there is sparse information available regarding their potential functional and biological significance in DM. This review article summarizes the current knowledge on the involvement of the main epigenetic alterations in the methylation status of Alu and LINE-1 retrotransposons and their potential role as epigenetic markers of global DNA methylation in the pathogenesis of DM. Full article

(This article belongs to the Collection Epigenetic Mechanisms in Diabetes Research)

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24 pages, 333 KiB

Open AccessReview

Decoding the Epigenetics of Infertility: Mechanisms, Environmental Influences, and Therapeutic Strategies

by Lara Saftić Martinović, Tea Mladenić, Dora Lovrić, Saša Ostojić and Sanja Dević Pavlić

Epigenomes 2024, 8(3), 34; https://doi.org/10.3390/epigenomes8030034 - 5 Sep 2024

Abstract

Infertility is a complex condition caused by a combination of genetic, environmental, and lifestyle factors. Recent advances in epigenetics have highlighted the importance of epigenetic changes in fertility regulation. This review aims to provide a comprehensive overview of the epigenetic mechanisms involved in [...] Read more.

Infertility is a complex condition caused by a combination of genetic, environmental, and lifestyle factors. Recent advances in epigenetics have highlighted the importance of epigenetic changes in fertility regulation. This review aims to provide a comprehensive overview of the epigenetic mechanisms involved in infertility, with a focus on DNA methylation, histone modification, and non-coding RNAs. We investigate the specific epigenetic events that occur during gametogenesis, with a focus on spermatogenesis and oogenesis as distinct processes. Furthermore, we investigate how environmental factors such as diet, stress, and toxin exposure can influence these epigenetic changes, potentially leading to infertility. The second part of the review explores epigenetic changes as therapeutic targets for infertility. Emerging therapies that modulate epigenetic marks present promising opportunities for fertility restoration, particularly in spermatogenesis. By summarizing current research findings, this review emphasizes the importance of understanding epigenetic contributions to infertility. Our discussion aims to lay the groundwork for future research directions and clinical applications in reproductive health. Full article

(This article belongs to the Collection Feature Papers in Epigenomes)

10 pages, 1727 KiB

Open AccessArticle

α-Crystalline Domains and Intrinsically Disordered Regions Can Work in Parallel to Induce Accumulation of MBD6 at Chromocenters in Arabidopsis thaliana

by Brandon A. Boone, Cristy P. Mendoza, Noah J. Behrendt and Steven E. Jacobsen

Epigenomes 2024, 8(3), 33; https://doi.org/10.3390/epigenomes8030033 - 28 Aug 2024

Abstract

Proteins are localized and concentrated at cellular and genomic locations for specific and efficient functions. Efforts to understand protein accumulation in eukaryotic organisms have primarily focused on multivalent interactions between intrinsically disordered regions (IDRs) as mediators of protein condensation. We previously showed that [...] Read more.

Proteins are localized and concentrated at cellular and genomic locations for specific and efficient functions. Efforts to understand protein accumulation in eukaryotic organisms have primarily focused on multivalent interactions between intrinsically disordered regions (IDRs) as mediators of protein condensation. We previously showed that α-crystalline domain (ACD) proteins 15 (ACD15) and 21 (ACD21) were required for multimerization and the accumulation of gene-silencing methyl-CpG-binding domain protein 6 (MBD6) at chromocenters in Arabidopsis thaliana. Here, we demonstrate that ACDs and IDRs can act as parallel mechanisms, facilitating higher-order MBD6 assemblies. Using human IDRs known to be important for protein accumulation, we replicated and enhanced the accumulation of MBD6 at chromocenters. In addition, IDRs fused to MBD6 could substitute for ACD function and partially reconstitute the MBD6 gene-silencing function. However, the accumulation of MBD6 by IDRs still required ACD15 and ACD21 for full effect. These results establish that ACD-mediated protein accumulation is a mechanism that can function similarly to and together with IDR-mediated mechanisms. Full article

(This article belongs to the Collection Epigenetic Control in Plants)

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IDRs can enhance MBD6 nuclear foci. (A) Cartoon schematic of MBD6 IDR chimeric proteins, made using BioRender.com. (B) Representative root nuclei demonstrating localization patterns of MBD6 or MBD6-IDR fusion proteins in either wild-type or acd15 acd21 mutant plants. Scale bar = 2 μM. (C) MBD6 nuclear foci counts across z-stacks of root tissue from multiple plant lines (N = 5 for each construct tested) in both wild-type and acd15 acd21 mutant plants. Statistically compared using one-way ANOVA with multi-comparisons using Dunnett’s test. (p values: **** < 0.0001, ** < 0.01, ns >= 0.05). Full article ">Figure 2
Synthetically accumulating MBD6 can mimic gene silencing. (A) Cartoon schematic of MBD6 IDR chimeric proteins, made using BioRender.com. (B) Representative image of root nuclei from mbd5 mbd6 mutant plants expressing MBD6 or MBD6-IDR fusion proteins. Scale bar = 2 μM. (C) Foci counts across the z-stack of mbd5 mbd6 mutant plants expressing either MBD6 or MBD6-IDR fusion proteins (N = 5 plants per construct). Statistically compared using one-way ANOVA with multiple comparisons using Dunnett’s comparison test. (p-value: *** < 0.001, ** < 0.01, ns >= 0.05). (D) FWA expression normalized to the mbd5 mbd6 mutant background from RT-qPCR. Statistically compared using one-way ANOVA with multiple comparisons using Dunnett’s comparison test. (p-value: **** < 0.0001, *** < 0.001, ns >= 0.05). Full article ">Figure 3
Model of MBD6 accumulation at methylated sites through endogenous and synthetic mechanisms (IDRs). The DNA methylation-binding protein, MBD6, can be synthetically hyper-accumulated using IDRs. However, ACD15 and ACD21 also control protein accumulation and can work together with these IDRs to maintain efficient MBD6 localization. Therefore, both mechanisms can functionally drive MBD6 accumulation. Made using BioRender. Full article ">

28 pages, 5546 KiB

Open AccessArticle

Genome-Wide Methylation Profiling of Peripheral T–Cell Lymphomas Identifies TRIP13 as a Critical Driver of Tumor Proliferation and Survival

by Pawel Nowialis, Julian Tobon, Katarina Lopusna, Jana Opavska, Arshee Badar, Duo Chen, Reem Abdelghany, Gene Pozas, Jacob Fingeret, Emma Noel, Alberto Riva, Hiroshi Fujiwara, Alexander Ishov and Rene Opavsky

Epigenomes 2024, 8(3), 32; https://doi.org/10.3390/epigenomes8030032 - 21 Aug 2024

Abstract

Cytosine methylation contributes to the regulation of gene expression and normal hematopoiesis in mammals. It is catalyzed by the family of DNA methyltransferases that include DNMT1, DNMT3A, and DNMT3B. Peripheral T–cell lymphomas (PTCLs) represent aggressive mature T–cell malignancies exhibiting a broad spectrum of [...] Read more.

Cytosine methylation contributes to the regulation of gene expression and normal hematopoiesis in mammals. It is catalyzed by the family of DNA methyltransferases that include DNMT1, DNMT3A, and DNMT3B. Peripheral T–cell lymphomas (PTCLs) represent aggressive mature T–cell malignancies exhibiting a broad spectrum of clinical features with poor prognosis and inadequately understood molecular pathobiology. To better understand the molecular landscape and identify candidate genes involved in disease maintenance, we profiled DNA methylation and gene expression of PTCLs. We found that the methylation patterns in PTCLs are deregulated and heterogeneous but share 767 hypo- and 567 hypermethylated differentially methylated regions (DMRs) along with 231 genes up- and 91 genes downregulated in all samples, suggesting a potential association with tumor development. We further identified 39 hypomethylated promoters associated with increased gene expression in the majority of PTCLs. This putative oncogenic signature included the TRIP13 (thyroid hormone receptor interactor 13) gene whose genetic and pharmacologic inactivation inhibited the proliferation of T–cell lines by inducing G2-M arrest and apoptosis. Our data thus show that human PTCLs have a significant number of recurrent methylation alterations that may affect the expression of genes critical for proliferation whose targeting might be beneficial in anti-lymphoma treatments. Full article

(This article belongs to the Special Issue New Insights into Epigenetic Regulation in Cancer)

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19 pages, 341 KiB

Open AccessArticle

Sex-Specific Associations between Prenatal Exposure to Bisphenols and Phthalates and Infant Epigenetic Age Acceleration

by Gillian England-Mason, Sarah M. Merrill, Jiaying Liu, Jonathan W. Martin, Amy M. MacDonald, David W. Kinniburgh, Nicole Gladish, Julia L. MacIsaac, Gerald F. Giesbrecht, Nicole Letourneau, Michael S. Kobor and Deborah Dewey

Epigenomes 2024, 8(3), 31; https://doi.org/10.3390/epigenomes8030031 - 10 Aug 2024

Abstract

We examined whether prenatal exposure to two classes of endocrine-disrupting chemicals (EDCs) was associated with infant epigenetic age acceleration (EAA), a DNA methylation biomarker of aging. Participants included 224 maternal–infant pairs from a Canadian pregnancy cohort study. Two bisphenols and 12 phthalate metabolites [...] Read more.

We examined whether prenatal exposure to two classes of endocrine-disrupting chemicals (EDCs) was associated with infant epigenetic age acceleration (EAA), a DNA methylation biomarker of aging. Participants included 224 maternal–infant pairs from a Canadian pregnancy cohort study. Two bisphenols and 12 phthalate metabolites were measured in maternal second trimester urines. Buccal epithelial cell cheek swabs were collected from 3 month old infants and DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The Pediatric-Buccal-Epigenetic tool was used to estimate EAA. Sex-stratified robust regressions examined individual chemical associations with EAA, and Bayesian kernel machine regression (BKMR) examined chemical mixture effects. Adjusted robust models showed that in female infants, prenatal exposure to total bisphenol A (BPA) was positively associated with EAA (B = 0.72, 95% CI: 0.21, 1.24), and multiple phthalate metabolites were inversely associated with EAA (Bs from −0.36 to −0.66, 95% CIs from −1.28 to −0.02). BKMR showed that prenatal BPA was the most important chemical in the mixture and was positively associated with EAA in both sexes. No overall chemical mixture effects or male-specific associations were noted. These findings indicate that prenatal EDC exposures are associated with sex-specific deviations in biological aging, which may have lasting implications for child health and development. Full article

(This article belongs to the Collection Feature Papers in Epigenomes)

20 pages, 1620 KiB

Open AccessReview

Unravelling the Epigenetic Code: DNA Methylation in Plants and Its Role in Stress Response

by Emanuela Talarico, Alice Zambelli, Fabrizio Araniti, Eleonora Greco, Adriana Chiappetta and Leonardo Bruno

Epigenomes 2024, 8(3), 30; https://doi.org/10.3390/epigenomes8030030 - 8 Aug 2024

Abstract

Environmental stress significantly affects plant growth, development, and survival. Plants respond to stressors such as temperature fluctuations, water scarcity, nutrient deficiencies, and pathogen attacks through intricate molecular and physiological adaptations. Epigenetic mechanisms are crucial in regulating gene expression in response to environmental stress. [...] Read more.

Environmental stress significantly affects plant growth, development, and survival. Plants respond to stressors such as temperature fluctuations, water scarcity, nutrient deficiencies, and pathogen attacks through intricate molecular and physiological adaptations. Epigenetic mechanisms are crucial in regulating gene expression in response to environmental stress. This review explores the current understanding of epigenetic modifications, including DNA methylation, and their roles in modulating gene expression patterns under environmental stress conditions. The dynamic nature of epigenetic modifications, their crosstalk with stress-responsive pathways, and their potential implications for plant adaptation and crop improvement are highlighted in the face of changing environmental conditions. Full article

(This article belongs to the Special Issue Plant Epigenome and Epitranscriptome Adaptation to Environmental Changes)

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Epigenetic regulation of cold and heat stress response and memory abiotic stress signals induce changes in epigenetic regulators’ expression and/or function, including methyltransferases, chromatin remodeling factors, and enzymes responsible for histone modification. The cold response induces a decrease in both 5mC and 6mA levels to confer freezing tolerance. It involves the activity of CBF TFs that bind to COR promoters to activate COR gene expression. Under heat stress conditions, transcription of the ONSEN retrotransposon is induced, and HSPs are activated following histone modifications of HSP genes. Some of these changes result in permanent epigenetic modifications that can be inherited, while others result in transient changes. The transient changes in chromatin facilitate the acclimation response, while the permanent epigenetic changes contribute to stress memory within and between generations. Full article ">Figure 2
Epigenetic regulation of stress response, memory, and tolerance to drought stress. In particular, it induces changes in the methylation status of several genes, including CYP450 genes. In addition, TFs, including some NACs, show a global decrease in methylation levels. Other TFs, such as WRKY and MYB, show altered expression levels after drought stress under TE control. Methylated transposons are often involved in the signaling pathways of several gene families known to be involved under abiotic stress conditions. These changes, which are involved in the stress response, may lead to the development of stress memory. Full article ">Figure 3
Epigenetic regulation of salt stress response, memory, and tolerance. In particular, plants exposed to salt stress show hypermethylation and hypomethylation of specific target genes. Cytosine hypermethylation was observed in the potassium transporters HKT2;1 and HKT2;3 and in the flavonol synthase genes FLS1 and WRS15. In addition, demethylase genes such as ROS, DML, DME, and BZ8 undergo strong changes in their expression. Some of these changes confer increased stress tolerance, which future progeny can inherit. Full article ">Figure 4
Plant responses to environmental stresses and the role of epigenetic control in plant growth plasticity. Plants are exposed to various environmental stresses that can affect growth and productivity. This exposure leads to plant stress responses and epigenetic regulation, which includes DNA methylation, histone modification, and miRNA regulation, which allows plants to attain stress memory. Understanding these fascinating features helps to identify targets for crop improvement. Full article ">

14 pages, 3079 KiB

Open AccessArticle

Multiomics Screening Identified CpG Sites and Genes That Mediate the Impact of Exposure to Environmental Chemicals on Cardiometabolic Traits

by Majid Nikpay

Epigenomes 2024, 8(3), 29; https://doi.org/10.3390/epigenomes8030029 - 29 Jul 2024

Abstract

An understanding of the molecular mechanism whereby an environmental chemical causes a disease is important for the purposes of future applications. In this study, a multiomics workflow was designed to combine several publicly available datasets in order to identify CpG sites and genes [...] Read more.

An understanding of the molecular mechanism whereby an environmental chemical causes a disease is important for the purposes of future applications. In this study, a multiomics workflow was designed to combine several publicly available datasets in order to identify CpG sites and genes that mediate the impact of exposure to environmental chemicals on cardiometabolic traits. Organophosphate and prenatal lead exposure were previously reported to change methylation level at the cg23627948 site. The outcome of the analyses conducted in this study revealed that, as the cg23627948 site becomes methylated, the expression of the GNA12 gene decreases, which leads to a higher body fat percentage. Prenatal perfluorooctane sulfonate exposure was reported to increase the methylation level at the cg21153102 site. Findings of this study revealed that higher methylation at this site contributes to higher diastolic blood pressure by changing the expression of CHP1 and GCHFR genes. Moreover, HKR1 mediates the impact of B12 supplementation → cg05280698 hypermethylation on higher kidney function, while CTDNEP1 mediates the impact of air pollution → cg03186999 hypomethylation on higher systolic blood pressure. This study investigates CpG sites and genes that mediate the impact of environmental chemicals on cardiometabolic traits. Furthermore, the multiomics approach described in this study provides a convenient workflow with which to investigate the impact of an environmental factor on the body’s biomarkers, and, consequently, on health conditions, using publicly available data. Full article

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21 pages, 676 KiB

Open AccessSystematic Review

DNA Methylation as Drug Sensitivity Marker in RCC: A Systematic Review

by Antonios Koudonas, Georgios Dimitriadis, Anastasios Anastasiadis and Maria Papaioannou

Epigenomes 2024, 8(3), 28; https://doi.org/10.3390/epigenomes8030028 - 15 Jul 2024

Abstract

Patient response after treatment of renal cell cancer (RCC) with systemic agents, which include various drug categories, is generally poor and unpredictable. In this context, the ideal drug administration includes tools to predict the sensitivity of the disease to therapy. The aim of [...] Read more.

Patient response after treatment of renal cell cancer (RCC) with systemic agents, which include various drug categories, is generally poor and unpredictable. In this context, the ideal drug administration includes tools to predict the sensitivity of the disease to therapy. The aim of this study was to systematically summarize the reports on the predictive value of the methylation status in the systemic therapy of RCC. Only original articles reporting on the association of promoter methylation with the response of patients or cell lines to systemic agents were included in this review. We applied PRISMA recommendations to the structure and methodology of this systematic review. Our literature search concluded with 31 articles conducted on RCC cell lines and patient tissues. The majority of the studies demonstrated a methylation-dependent response to systemic agents. This correlation suggests that the methylation pattern can be used as a predictive tool in the management of RCC with various classes of systemic agents. However, although methylation biomarkers show promise for predicting response, the evidence of such correlation is still weak. More studies on the gene methylation pattern in patients under systemic therapy and its correlation with different degrees of response are needed. Full article

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15 pages, 3033 KiB

Open AccessReview

Irradiation and Alterations in Hippocampal DNA Methylation

by Soren Impey and Jacob Raber

Epigenomes 2024, 8(3), 27; https://doi.org/10.3390/epigenomes8030027 - 5 Jul 2024

Abstract

The response of the brain to radiation is important for cancer patients receiving whole or partial brain irradiation or total body irradiation, those exposed to irradiation as part of a nuclear accident or a nuclear war or terrorism event, and for astronauts during [...] Read more.

The response of the brain to radiation is important for cancer patients receiving whole or partial brain irradiation or total body irradiation, those exposed to irradiation as part of a nuclear accident or a nuclear war or terrorism event, and for astronauts during and following space missions. The mechanisms mediating the effects of irradiation on the hippocampus might be associated with alterations in hippocampal DNA methylation. Changes in cytosine methylation involving the addition of a methyl group to cytosine (5 mC) and especially those involving the addition of a hydroxy group to 5 mC (hydroxymethylcytosine or 5 hmC) play a key role in regulating the expression of genes required for hippocampal function. In this review article, we will discuss the effects of radiation on hippocampal DNA methylation and whether these effects are associated with hippocampus-dependent cognitive measures and molecular measures in the hippocampus involved in cognitive measures. We will also discuss whether the radiation-induced changes in hippocampal DNA methylation show an overlap across different doses of heavy ion irradiation and across irradiation with different ions. We will also discuss whether the DNA methylation changes show a tissue-dependent response. Full article

(This article belongs to the Collection Feature Papers in Epigenomes)

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Following exposure to ionizing irradiation as part of cancer treatment, a nuclear attack or incident at a power plant, or space missions, effects on DNA methylation in and outside the brain might involve the bi-directional gut–brain axis and reactive oxygen species (ROS) in mitochondria. Irradiation has been shown to increase the hippocampal levels of the DNMT3, TET 1, and TET 3 enzymes involved in DNA methylation. Alterations in levels of 5 mC and 5 hmC, in turn, might be related to the increased levels of the injury markers 8-OHDG and 4-HNE observed following irradiation. Figure was generated using Biorender.com software. Full article ">Figure 2
Methylation and demethylation mechanisms. (A) Diagram depicts methyltransferase enzymes and their functional roles, as well as the TET family of methyl-hydroxylases. (B) TET-family enzymes actively demethylate 5mC via step-wise oxidation followed by TDG-mediated glycosylation and base-excision repair of the abasic site to cytosine. Figure was generated using Biorender.com software. Full article ">Figure 3
Radiation studies in cancer patients and in preclinical models have highlighted that therapeutic strategies to control the tumor are often associated with behavioral alterations and cognitive injury, involving detrimental effects on synaptic function. It is recognized that simulated space irradiation is not only pertinent to astronauts during and following missions. There is increasing interest in the use of radiation as part of the space environment in cancer therapy, including the use of protons and carbon in cancer patients. Detrimental effects on the blood–brain barrier and neuroinflammation might be a large contributor to these detrimental effects as well. These detrimental effects are not limited to radiation therapy and are often seen following chemotherapy and immunotherapy as well. The effects of radiation on the brain, including those of often-used clinical radiation and simulated space irradiation, are associated with epigenetic alterations. The gut–brain axis and ROS might play a role in these pathways. Figure was generated using Biorender.com software. Full article ">Figure 4
Diagram depicting proteins that bind to methylated DNA, sorted by the type of methylation. A “?” denotes conflicting evidence or a lack of validation by other studies. For 5mC, we have also indicated whether the protein interacts with CpG or CpA sites. Figure was generated using Biorender.com software. Full article ">Figure 5
Behavioral and cognitive tests are often used to assess the effects of irradiation on the brain. Historically, the hippocampus has been the focus of studies assessing the effects of irradiation on the brain. For example, neurogenesis has been studied, and based on the susceptibility of the hippocampus to radiation effects, hippocampal sparing is being considered in radiation therapy. However, it is recognized that the effects of irradiation are seen at doses below those affecting neurogenesis. The quality of nest building is considered a measure related to the activities of daily life for humans. In the water maze, spatial navigation to a visible or hidden platform or spatial memory retention in a probe trial (no platform) is assessed. Fear learning and memory can be assessed in the fear conditioning test. Depending on the design, either hippocampus-dependent contextual and/or hippocampus-independent cued fear conditioning is assessed. In the acoustic startle response test, the response to an acoustic stimulus, sometimes in the presence of another aversive stimulus, is assessed. In the Y maze, hippocampus-dependent spatial alternation is assessed in a single trial. In the spatial Y maze version of this test, there are two trials. In the first trial, access to one arm is blocked. Following a delay, access to the originally blocked arm is made available, and visits to that arm and entries into that arm are analyzed. Alterations in behavioral and cognitive performance following irradiation are associated with epigenetic changes in pertinent brain regions. These epigenetic effects are not limited to the brain and are also seen in other tissues following irradiation. Figure was generated using Biorender.com software. Full article ">Figure 6
Methodologies for genome-wide profiling of cytosine methylation. Bisulfite converts non-methylated bases to uracil, which is then converted to thymidine via library amplification. Conventional bisulfite-Seq fails to distinguish 5mC from 5hmC. TAB-Seq and other related approaches use β glucosyltransferase (βGT) to protect 5hmC, followed by enzymatic or chemical conversion of non-protected bases. In the case of TAB-Seq, TET is used to sequentially oxidize 5mC, followed by bisulfite treatment, which converts the resulting 5caC or 5fC to uracil but spares the protected 5hmC. MeDIP-Seq and MBD-Seq use antibodies, or methyl-binding domains, to pull down methylated chromatin fragments. MeDIP-Seq can interrogate 5mC, 5hmC, 5fc, or 5caC through the use of specific antibodies. MRE-Seq digests DNA with restriction enzymes that cut specific CpG sequences or are blocked by methylation of these CpG sequences. Sites that are resistant to digestion are scored as methylated. Recently, “nanopore” sequencing of DNA has been used to create genome-wide maps of 5mC and 5hmC at single-nucleotide resolution. Figure was generated using Biorender.com software. Full article ">Figure 7
Selected genes from the “synapse” gene ontology were associated with increased 5hmC following 65Fe and 28Si irradiation of the mouse hippocampus. The genes highlighted in purple are radiation signature genes that were associated with increased 5hmc in response to a proton, 65Fe, or 28Si irradiation. Data were adapted and selected from [<a href="#B39-epigenomes-08-00027" class="html-bibr">39</a>]. Full article ">

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