Epigenomes最新文献

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.

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.

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.

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.

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.

(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.

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.

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.

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.

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.