scholarly journals Distinct chromatin signatures of DNA hypomethylation in aging and cancer

2017 ◽  
Author(s):  
Raúl F. Pérez ◽  
Juan Ramón Tejedor ◽  
Gustavo F. Bayón ◽  
Agustín F. Fernández ◽  
Mario F. Fraga
Keyword(s):  
Dna Methylation ◽  
Dna Sequences ◽  
Es Cells ◽  
Gene Promoters ◽  
Dna Hypomethylation ◽  
Chromatin Signature ◽  
Unknown Gene ◽  
Genomic Regions ◽  
Nih Roadmap

AbstractBackgroundCancer is an aging-associated disease but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, any similarities of the regions where this loss of DNA methylation occurs is currently not well characterized, nor is it known whether such regions also share a common chromatin signature in aging and cancer.ResultsTo address this issue we analysed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain and lung tumors and healthy blood, and integrated the results with histone, chromatin state and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging, and 286,746 in cancer. Hyper- and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue-independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, whilst in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark.ConclusionsOur results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.

DNA methylation in satellite repeats disorders

2019 ◽  
Vol 63 (6) ◽  
pp. 757-771 ◽  
Author(s):  
Claire Francastel ◽  
Frédérique Magdinier
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Repetitive Dna ◽  
Dna Sequences ◽  
Satellite Repeats ◽  
Tremendous Progress ◽  
Genes Encoding ◽  
Dna Elements ◽  
Near Future

Abstract Despite the tremendous progress made in recent years in assembling the human genome, tandemly repeated DNA elements remain poorly characterized. These sequences account for the vast majority of methylated sites in the human genome and their methylated state is necessary for this repetitive DNA to function properly and to maintain genome integrity. Furthermore, recent advances highlight the emerging role of these sequences in regulating the functions of the human genome and its variability during evolution, among individuals, or in disease susceptibility. In addition, a number of inherited rare diseases are directly linked to the alteration of some of these repetitive DNA sequences, either through changes in the organization or size of the tandem repeat arrays or through mutations in genes encoding chromatin modifiers involved in the epigenetic regulation of these elements. Although largely overlooked so far in the functional annotation of the human genome, satellite elements play key roles in its architectural and topological organization. This includes functions as boundary elements delimitating functional domains or assembly of repressive nuclear compartments, with local or distal impact on gene expression. Thus, the consideration of satellite repeats organization and their associated epigenetic landmarks, including DNA methylation (DNAme), will become unavoidable in the near future to fully decipher human phenotypes and associated diseases.

scholarly journals Role of CxxC-finger protein 1 in establishing mouse oocyte epigenetic landscapes

2021 ◽  
Author(s):  
Qian-Qian Sha ◽  
Ye-Zhang Zhu ◽  
Yunlong Xiang ◽  
Jia-Li Yu ◽  
Xiao-Ying Fan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone H3 ◽  
Finger Protein ◽  
Maternal Genome ◽  
Wide Range ◽  
Transcriptional Changes ◽  
Nuclear Events ◽  
Genomic Regions ◽  
Cxxc Finger Protein 1

Abstract During oogenesis, oocytes gain competence and subsequently undergo meiotic maturation and prepare for embryonic development; trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1) impairs H3K4me3 accumulation and causes changes in chromatin configurations. This study investigated the changes in genomic H3K4me3 landscapes in oocytes with Cxxc1 knockout and the effects on other epigenetic factors such as the DNA methylation, H3K27me3, H2AK119ub1 and H3K36me3. H3K4me3 is overall decreased after knocking out Cxxc1, including both the promoter region and the gene body. CXXC1 and MLL2, which is another histone H3 methyltransferase, have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. Cxxc1 deletion caused a decrease in DNA methylation levels and affected H3K27me3 and H2AK119ub1 distributions, particularly at regions with high DNA methylation levels. The changes in epigenetic networks implicated by Cxxc1 deletion were correlated with the transcriptional changes in genes in the corresponding genomic regions. This study elucidates the epigenetic changes underlying the phenotypes and molecular defects in oocytes with deleted Cxxc1 and highlights the role of CXXC1 in orchestrating multiple factors that are involved in establishing the appropriate epigenetic states of maternal genome.

scholarly journals Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer

2021 ◽  
Author(s):  
Jean S Fain ◽  
Axelle Loriot ◽  
Anna Diacofotaki ◽  
Aurelie Van Tongelen ◽  
Charles De Smet
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Tumor Development ◽  
Epigenetic Mark ◽  
Dna Hypomethylation ◽  
Dna Hypermethylation ◽  
Bioinformatics Analyses ◽  
Genomic Regions ◽  
Methylation Patterns

DNA methylation is an epigenetic mark associated with gene repression. It is now well established that tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) of methylation marks in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark known to be deposited during progression of the transcription machinery and to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of increased DNA methylation in the MAGEA6/GABRA3 locus. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo- and hypermethylation. In several of these loci, DNA hypermethylation affected tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.

scholarly journals Epigenetic Deregulation of Telomere-Related Genes in Newly Diagnosed Multiple Myeloma Patients

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6348
Author(s):  
Samrat Roy Choudhury ◽  
Cody Ashby ◽  
Fenghuang Zhan ◽  
Frits van Rhee
Keyword(s):  
Dna Methylation ◽  
Multiple Myeloma ◽  
Dna Sequences ◽  
Critical Length ◽  
Newly Diagnosed ◽  
Genome Wide ◽  
Healthy Donors ◽  
Binding Factor ◽  
G Quadruplex

High-risk Multiple Myeloma (MM) patients were found to maintain telomere length (TL), below the margin of short critical length, consistent with proactive overexpression of telomerase. Previously, DNA methylation has been shown as a determinant of telomere-related gene (TRG) expression and TL to assess risk in different types of cancer. We mapped genome-wide DNA methylation in a cohort of newly diagnosed MM (NDMM; n = 53) patients of major molecular subgroups, compared to age-matched healthy donors (n = 4). Differential methylation and expression at TRG-loci were analyzed in combination with overlapping chromatin marks and underlying DNA-sequences. We observed a strong correlation (R2 ≥ 0.5) between DNA methylation and expression amongst selective TRGs, such that demethylation at the promoters of DDX1 and TERF1 were associated to their oncogenic upregulation, while demethylation at the bodies of two key tumor suppressors ZNF208 and RAP1A led to downregulation of the genes. We demonstrated that TRG expression may be controlled by DNA methylation alone or in cooperation with chromatin modifications or CCCTC-binding factor at the regulatory regions. Additionally, we showed that hypomethylated DMRs of TRGs in NDMM are stabilized with G-quadruplex forming sequences, suggesting a crucial role of these epigenetically vulnerable loci in MM pathogenesis. We have identified a panel of five TRGs, which are epigenetically deregulated in NDMM patients and may serve as early detection biomarkers or therapeutic targets in the disease.

scholarly journals Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jean S. Fain ◽  
Axelle Loriot ◽  
Anna Diacofotaki ◽  
Aurélie Van Tongelen ◽  
Charles De Smet
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Tumor Development ◽  
Transcriptional Elongation ◽  
Dna Hypomethylation ◽  
Dna Hypermethylation ◽  
Bioinformatics Analyses ◽  
Genomic Regions ◽  
Methylation Patterns

AbstractTumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark deposited during transcriptional elongation and known to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of regional DNA hypermethylation. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo/hypermethylation, and some of these included tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.

scholarly journals Lsh Is Essential for Maintaining Global DNA Methylation Levels in Amphibia and Fish and Interacts Directly with Dnmt1

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Donncha S. Dunican ◽  
Sari Pennings ◽  
Richard R. Meehan
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Repetitive Sequences ◽  
Global Dna Methylation ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Mouse Cells ◽  
Eukaryotic Genomes

Eukaryotic genomes are methylated at cytosine bases in the context of CpG dinucleotides, a pattern which is maintained through cell division by the DNA methyltransferase Dnmt1. Dramatic methylation losses are observed in plant and mouse cells lacking Lsh (lymphoid specific helicase), predominantly at repetitive sequences and gene promoters. However, the mechanism by which Lsh contributes to the maintenance of DNA methylation is unknown. Here we show that DNA methylation is lost in Lsh depleted frog and fish embryos, both of which exhibit developmental delay. Additionally, we show that both Lsh and Dnmt1 are associated with chromatin and that Lsh knockdown leads to a decreased Dnmt1-chromatin association. Coimmunoprecipitation experiments reveal that Lsh and Dnmt1 are found in the same protein complex, and pulldowns show this interaction is direct. Our data indicate that Lsh is usually diffuse in the nucleus but can be recruited to heterochromatin in a HP1α-dependent manner. These data together (a) show that the role of Lsh in DNA methylation is conserved in plants, amphibian, fish, and mice and (b) support a model in which Lsh contributes to Dnmt1 binding to chromatin, explaining how its loss can potentially lead to perturbations in DNA methylation maintenance.

Non-canonical functions of the DNA methylome in gene regulation

2013 ◽  
Vol 451 (1) ◽  
pp. 13-23 ◽  
Author(s):  
James P. Reddington ◽  
Sari Pennings ◽  
Richard R. Meehan
Keyword(s):  
Dna Methylation ◽  
Gene Regulation ◽  
Transcriptional Regulation ◽  
Polycomb Group ◽  
Epigenetic Mark ◽  
Regulation Of Transcription ◽  
Gene Promoters ◽  
Dna Modification ◽  
Dna Methylome ◽  
Genomic Regions

Methylation of the cytosine base in DNA, DNA methylation, is an essential epigenetic mark in mammals that contributes to the regulation of transcription. Several advances have been made in this area in recent years, leading to a leap forward in our understanding of how this pathway contributes to gene regulation during embryonic development, and the functional consequences of its perturbation in human disease. Critical to these advances is a comprehension of the genomic distribution of modified cytosine bases in unprecedented detail, drawing attention to genomic regions beyond gene promoters. In addition, we have a more complete understanding of the multifactorial manner by which DNA methylation influences gene regulation at the molecular level, and which genes rely directly on the DNA methylome for their normal transcriptional regulation. It is becoming apparent that a major role of DNA modification is to act as a relatively stable, and mitotically heritable, template that contributes to the establishment and maintenance of chromatin states. In this regard, interplay is emerging between DNA methylation and the PcG (Polycomb group) proteins, which act as evolutionarily conserved mediators of cell identity. In the present paper we review these aspects of DNA methylation, and discuss how a multifunctional view of DNA modification as an integral part of chromatin organization is influencing our understanding of this epigenetic mark's contribution to transcriptional regulation.

scholarly journals Accumulation of transposable elements in Hox gene clusters during adaptive radiation of Anolis lizards

2016 ◽  
Vol 283 (1840) ◽  
pp. 20161555 ◽  
Author(s):  
Nathalie Feiner
Keyword(s):  
Transposable Elements ◽  
Dna Sequences ◽  
Adaptive Radiation ◽  
Genome Structure ◽  
Gene Clusters ◽  
Genomic Region ◽  
High Rate ◽  
Morphological Adaptations ◽  
Genomic Regions

Transposable elements (TEs) are DNA sequences that can insert elsewhere in the genome and modify genome structure and gene regulation. The role of TEs in evolution is contentious. One hypothesis posits that TE activity generates genomic incompatibilities that can cause reproductive isolation between incipient species. This predicts that TEs will accumulate during speciation events. Here, I tested the prediction that extant lineages with a relatively high rate of speciation have a high number of TEs in their genomes. I sequenced and analysed the TE content of a marker genomic region ( Hox clusters) in Anolis lizards, a classic case of an adaptive radiation. Unlike other vertebrates, including closely related lizards, Anolis lizards have high numbers of TEs in their Hox clusters, genomic regions that regulate development of the morphological adaptations that characterize habitat specialists in these lizards. Following a burst of TE activity in the lineage leading to extant Anolis , TEs have continued to accumulate during or after speciation events, resulting in a positive relationship between TE density and lineage speciation rate. These results are consistent with the prediction that TE activity contributes to adaptive radiation by promoting speciation. Although there was no evidence that TE density per se is associated with ecological morphology, the activity of TEs in Hox clusters could have been a rich source for phenotypic variation that may have facilitated the rapid parallel morphological adaptation to microhabitats seen in extant Anolis lizards.

scholarly journals TET2 Inhibits Differentiation of Embryonic Stem Cells but Does Not Overcome Methylation-Induced Gene Silencing

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Louis Norman ◽  
Paul Tarrant ◽  
Timothy Chevassut
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Genomic Dna ◽  
Es Cells ◽  
Embryonic Stem ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Promoter Sequences ◽  
Maintenance Methylation

TET2 is a methylcytosine dioxygenase that is frequently mutated in myeloid malignancies, notably myelodysplasia and acute myeloid leukemia. TET2 catalyses the conversion of 5′-methylcytosine to 5′-hydroxymethylcytosine within DNA and has been implicated in the process of genomic demethylation. However, the mechanism by which TET2 loss of function results in hematopoietic dysplasia and leukemogenesis is poorly understood. Here, we show that TET2 is expressed in undifferentiated embryonic stem cells and that its knockdown results in reduction of 5′-hydroxymethylcytosine in genomic DNA. We also present DNA methylation data from bone marrow samples obtained from patients with TET2-mutated myelodysplasia. Based on these findings, we sought to identify the role of TET2 in regulating pluripotency and differentiation. We show that overexpression of TET2 in a stably integrated transgene leads to increased alkaline phosphatase expression in differentiating ES cells and impaired differentiation in methylcellulose culture. We speculate that this effect is due to TET2-mediated expression of stem cell genes in ES cells via hydroxylation of 5′-methylcytosines at key promoter sequences within genomic DNA. This leads to relative hypomethylation of gene promoters as 5′-hydroxymethylcytosine is not a substrate for DNMT1-mediated maintenance methylation. We sought to test this hypothesis by cotransfecting the TET2 gene with methylated reporter genes. The results of these experiments are presented.

scholarly journals The Role of lncRNAs in the Pathobiology and Clinical Behavior of Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1976
Author(s):  
Arantxa Carrasco-León ◽  
Ane Amundarain ◽  
Nahia Gómez-Echarte ◽  
Felipe Prósper ◽  
Xabier Agirre
Keyword(s):  
De Novo ◽  
Genetic Alterations ◽  
Dna Hypomethylation ◽  
Incurable Disease ◽  
Intergenic Regions ◽  
Hematological Neoplasm ◽  
Non Coding Rnas ◽  
Genomic Regions ◽  
Functional Mechanisms

MM is a hematological neoplasm that is still considered an incurable disease. Besides established genetic alterations, recent studies have shown that MM pathogenesis is also characterized by epigenetic aberrations, such as the gain of de novo active chromatin marks in promoter and enhancer regions and extensive DNA hypomethylation of intergenic regions, highlighting the relevance of these non-coding genomic regions. A recent study described how long non-coding RNAs (lncRNAs) correspond to 82% of the MM transcriptome and an increasing number of studies have demonstrated the importance of deregulation of lncRNAs in MM. In this review we focus on the deregulated lncRNAs in MM, including their biological or functional mechanisms, their role as biomarkers to improve the prognosis and monitoring of MM patients, and their participation in drug resistance. Furthermore, we also discuss the evidence supporting the role of lncRNAs as therapeutic targets through different novel RNA-based strategies.

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