scholarly journals DNA methylation marks inter-nucleosome linker regions throughout the human genome

2013 ◽  
Author(s):  
Benjamin P. Berman ◽  
Yaping Liu ◽  
Theresa K. Kelly
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
A Genome ◽  
Sequencing Studies

Background: Nucleosome organization and DNA methylation are two mechanisms that are important for proper control of mammalian transcription, as well as epigenetic dysregulation associated with cancer. Whole-genome DNA methylation sequencing studies have found that methylation levels in the human genome show periodicities of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we analyzed a number of published datasets and found a more compelling alternative explanation, namely that methylation levels are highest in linker regions between nucleosomes. Results: Reanalyzing the data from (Chodavarapu et al., 2010), we found that nucleosome-associated methylation could be strongly confounded by known sequence-related biases of the next-generation sequencing technologies. By accounting for these biases and using an unrelated nucleosome profiling technology, NOMe-seq, we found that genome-wide methylation was actually highest within linker regions occurring between nucleosomes in multi-nucleosome arrays. This effect was consistent among several methylation datasets generated independently using two unrelated methylation assays. Linker-associated methylation was most prominent within long Partially Methylated Domains (PMDs) and the positioned nucleosomes that flank CTCF binding sites. CTCF adjacent nucleosomes retained the correct positioning in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper nucleosomes positioning. Conclusions: The biological mechanisms responsible for DNA methylation patterns outside of gene promoters remain poorly understood. We identified a significant genome-wide relationship between nucleosome organization and DNA methylation, which can be used to more accurately analyze and understand the epigenetic changes that accompany cancer and other diseases.

scholarly journals DNA methylation marks inter-nucleosome linker regions throughout the human genome

2013 ◽  
Author(s):  
Benjamin P. Berman ◽  
Yaping Liu ◽  
Theresa K. Kelly
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
A Genome ◽  
Sequencing Studies

Background: Nucleosome organization and DNA methylation are two mechanisms that are important for proper control of mammalian transcription, as well as epigenetic dysregulation associated with cancer. Whole-genome DNA methylation sequencing studies have found that methylation levels in the human genome show periodicities of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we analyzed a number of published datasets and found a more compelling alternative explanation, namely that methylation levels are highest in linker regions between nucleosomes. Results: Reanalyzing the data from (Chodavarapu et al., 2010), we found that nucleosome-associated methylation could be strongly confounded by known sequence-related biases of the next-generation sequencing technologies. By accounting for these biases and using an unrelated nucleosome profiling technology, NOMe-seq, we found that genome-wide methylation was actually highest within linker regions occurring between nucleosomes in multi-nucleosome arrays. This effect was consistent among several methylation datasets generated independently using two unrelated methylation assays. Linker-associated methylation was most prominent within long Partially Methylated Domains (PMDs) and the positioned nucleosomes that flank CTCF binding sites. CTCF adjacent nucleosomes retained the correct positioning in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper nucleosomes positioning. Conclusions: The biological mechanisms responsible for DNA methylation patterns outside of gene promoters remain poorly understood. We identified a significant genome-wide relationship between nucleosome organization and DNA methylation, which can be used to more accurately analyze and understand the epigenetic changes that accompany cancer and other diseases.

scholarly journals DNA methylation marks inter-nucleosome linker regions throughout the human genome

2013 ◽  
Author(s):  
Benjamin P. Berman ◽  
Yaping Liu ◽  
Theresa K. Kelly
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
A Genome ◽  
Sequencing Studies

Background: Nucleosome organization and DNA methylation are two mechanisms that are important for proper control of mammalian transcription, as well as epigenetic dysregulation associated with cancer. Whole-genome DNA methylation sequencing studies have found that methylation levels in the human genome show periodicities of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we analyzed a number of published datasets and found a more compelling alternative explanation, namely that methylation levels are highest in linker regions between nucleosomes. Results: Reanalyzing the data from (Chodavarapu et al., 2010), we found that nucleosome-associated methylation could be strongly confounded by known sequence-related biases of the next-generation sequencing technologies. By accounting for these biases and using an unrelated nucleosome profiling technology, NOMe-seq, we found that genome-wide methylation was actually highest within linker regions occurring between nucleosomes in multi-nucleosome arrays. This effect was consistent among several methylation datasets generated independently using two unrelated methylation assays. Linker-associated methylation was most prominent within long Partially Methylated Domains (PMDs) and the positioned nucleosomes that flank CTCF binding sites. CTCF adjacent nucleosomes retained the correct positioning in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper nucleosomes positioning. Conclusions: The biological mechanisms responsible for DNA methylation patterns outside of gene promoters remain poorly understood. We identified a significant genome-wide relationship between nucleosome organization and DNA methylation, which can be used to more accurately analyze and understand the epigenetic changes that accompany cancer and other diseases.

scholarly journals DNA methylation marks inter-nucleosome linker regions throughout the human genome

2013 ◽  
Author(s):  
Benjamin P. Berman ◽  
Yaping Liu ◽  
Theresa K. Kelly
Keyword(s):  
Dna Methylation ◽  
Binding Sites ◽  
Ctcf Binding ◽  
Cpg Dinucleotides ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
A Genome ◽  
Sequencing Studies ◽  
Methylation Patterns

Nucleosome organization and DNA methylation are two epigenetic mechanisms that are important for proper control of mammalian transcription. Numerous lines of evidence suggest an interaction between these two mechanisms, but the nature of this interaction in vivo remains elusive. Whole-genome DNA methylation sequencing studies have shown that human methylation levels are periodic at intervals of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we propose an alternate explanation for these nucleosomal periodicities. By examining methylation patterns in published datasets, we find that genome-wide methylation levels are highest within the linker regions that occur between nucleosomes in multi-nucleosome arrays. This effect is most prominent within long-range Partially Methylated Domains (PMDs) and the strongly positioned nucleosomes that flank CTCF binding sites. The CTCF-flanking nucleosomes retain positioning even in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper positioning. We propose that DNA methylation is inhibited by histone proteins at CTCF and other unknown classes of nucleosomes within PMDs.

scholarly journals Genomic properties of variably methylated retrotransposons in mouse

Mobile DNA ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jessica L. Elmer ◽  
Amir D. Hay ◽  
Noah J. Kessler ◽  
Tessa M. Bertozzi ◽  
Eve A. C. Ainscough ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tissue Specificity ◽  
Cytosine Methylation ◽  
Individual Variability ◽  
Endogenous Retroviruses ◽  
Ctcf Binding ◽  
Genome Wide ◽  
A Genome ◽  
Physical Interactions ◽  
Intracisternal A Particle

Abstract Background Transposable elements (TEs) are enriched in cytosine methylation, preventing their mobility within the genome. We previously identified a genome-wide repertoire of candidate intracisternal A particle (IAP) TEs in mice that exhibit inter-individual variability in this methylation (VM-IAPs) with implications for genome function. Results Here we validate these metastable epialleles and discover a novel class that exhibit tissue specificity (tsVM-IAPs) in addition to those with uniform methylation in all tissues (constitutive- or cVM-IAPs); both types have the potential to regulate genes in cis. Screening for variable methylation at other TEs shows that this phenomenon is largely limited to IAPs, which are amongst the youngest and most active endogenous retroviruses. We identify sequences enriched within cVM-IAPs, but determine that these are not sufficient to confer epigenetic variability. CTCF is enriched at VM-IAPs with binding inversely correlated with DNA methylation. We uncover dynamic physical interactions between cVM-IAPs with low methylation ranges and other genomic loci, suggesting that VM-IAPs have the potential for long-range regulation. Conclusion Our findings indicate that a recently evolved interplay between genetic sequence, CTCF binding, and DNA methylation at young TEs can result in inter-individual variability in transcriptional outcomes with implications for phenotypic variation.

scholarly journals Genomic properties of variably methylated retrotransposons in mouse

2020 ◽  
Author(s):  
Jessica L. Elmer ◽  
Amir D. Hay ◽  
Noah J. Kessler ◽  
Tessa M. Bertozzi ◽  
Eve Ainscough ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tissue Specificity ◽  
Cytosine Methylation ◽  
Individual Variability ◽  
Endogenous Retroviruses ◽  
Ctcf Binding ◽  
Genome Wide ◽  
A Genome ◽  
Physical Interactions ◽  
Intracisternal A Particle

AbstractTransposable elements (TEs) are enriched in cytosine methylation, preventing their mobility within the genome. We previously identified a genome-wide repertoire of candidate intracisternal A particle (IAP) TEs in mice that exhibit inter-individual variability in this methylation (VM-IAPs) with implications for genome function. Here we validate these metastable epialleles and discover a novel class that exhibit tissue specificity (tsVM-IAPs) in addition to those with uniform methylation in all tissues (constitutive- or cVM-IAPs); both types have the potential to regulate genes in cis. Screening for variable methylation at other TEs shows that this phenomenon is largely limited to IAPs, which are amongst the youngest and most active endogenous retroviruses. We identify sequences enriched within cVM-IAPs, but determine that these are not sufficient to confer epigenetic variability. CTCF is enriched at VM-IAPs with binding inversely correlated with DNA methylation. We uncover dynamic physical interactions between cVM-IAPs with low methylation ranges and other genomic loci, suggesting that VM-IAPs have the potential for long-range regulation. Our findings indicate that a recently evolved interplay between genetic sequence, CTCF binding, and DNA methylation at young TEs can result in inter-individual variability in transcriptional outcomes with implications for phenotypic variation.

scholarly journals Modulation of Cellular CpG DNA Methylation by Kaposi's Sarcoma-Associated Herpesvirus

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Guy Journo ◽  
Carmel Tushinsky ◽  
Asia Shterngas ◽  
Nir Avital ◽  
Yonatan Eran ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Cpg Methylation ◽  
Gene Promoters ◽  
Methylation Analysis ◽  
Kshv Infection ◽  
Genome Wide ◽  
Infected Cells

ABSTRACTKaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) is a gammaherpesvirus associated with several human malignancies. DNA methylation at CpG dinucleotides is an epigenetic mark dysregulated in many cancer types and in KSHV-infected cells. Several previous studies have analyzed in detail the CpG methylation of the KSHV episomal genomes, but little is known about the impact of KSHV on the human genome. Our knowledge of cellular CpG methylation in the context of KSHV infection is currently limited to four hypermethylated human gene promoters. Therefore, we undertook a comprehensive CpG methylation analysis of the human methylome in KSHV-infected cells and KSHV-associated primary effusion lymphoma (PEL). We performed Infinium HumanMethylation450K and MethylationEpic BeadChip arrays and identified panels of hyper- and hypomethylated cellular promoters in KSHV-infected cells. We combined our genome-wide methylation analysis with high-throughput RNA sequencing (RNA-seq) to add functional outcomes to the virally induced methylation changes. We were able to correlate many downregulated genes with promoter hypermethylation and upregulated genes with hypomethylation. In addition, we show that treating the cells with a demethylating agent leads to reexpression of these downregulated genes, indicating that, indeed, DNA methylation plays a role in the repression of these human genes. Comparison betweende novoinfection and PEL suggests that the virus induces initial hypermethylation followed by a slow increase in genome-wide hypomethylation. This study extends our understanding of the relationship between epigenetic changes induced by KSHV infection and tumorigenesis.IMPORTANCEIn cancer cells, certain promoters become aberrantly methylated, contributing to the phenotype of the tumor. KSHV infection seems to modify cellular CpG methylation, but only a few methylated promoters have been identified in KSHV-infected cells. Here, we investigated the CpG methylation of the human genome in KSHV-associated primary effusion lymphoma (PEL) and KSHV-infected cells. We have identified many hyper- and hypomethylated gene promoters and correlated their methylation with cellular gene expression. These differentially methylated cellular promoters can distinguish KSHV-positive cells from uninfected cells and may serve as the foundation for the use of these differentially methylated regions as potential biomarkers for KSHV-associated malignancies. Drugs that reverse these cancerous methylation patterns have the potential to inhibit tumor growth. Here, we show that treating PEL cells with a demethylating drug (5-aza-2′-deoxycytidine) led to inhibition of cell growth, raising the possibility of testing this drug for the treatment of PEL.

scholarly journals DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 441
Author(s):  
Fanny Pineau ◽  
Davide Caimmi ◽  
Sylvie Taviaux ◽  
Maurane Reveil ◽  
Laura Brosseau ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dna Methylation ◽  
Clinical Trials ◽  
Lung Disease ◽  
Disease Severity ◽  
Genome Wide ◽  
A Genome ◽  
Lung Disease Severity ◽  
Epigenetic Biomarker

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

scholarly journals DNA Methylation in Solid Tumors: Functions and Methods of Detection

2021 ◽  
Vol 22 (8) ◽  
pp. 4247
Author(s):  
Andrea Martisova ◽  
Jitka Holcakova ◽  
Nasim Izadi ◽  
Ravery Sebuyoya ◽  
Roman Hrstka ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Solid Tumors ◽  
Epigenetic Modification ◽  
Single Gene ◽  
Restriction Enzymes ◽  
Methylation Analysis ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Genome Level ◽  
Dna Methylation Analysis

DNA methylation, i.e., addition of methyl group to 5′-carbon of cytosine residues in CpG dinucleotides, is an important epigenetic modification regulating gene expression, and thus implied in many cellular processes. Deregulation of DNA methylation is strongly associated with onset of various diseases, including cancer. Here, we review how DNA methylation affects carcinogenesis process and give examples of solid tumors where aberrant DNA methylation is often present. We explain principles of methods developed for DNA methylation analysis at both single gene and whole genome level, based on (i) sodium bisulfite conversion, (ii) methylation-sensitive restriction enzymes, and (iii) interactions of 5-methylcytosine (5mC) with methyl-binding proteins or antibodies against 5mC. In addition to standard methods, we describe recent advances in next generation sequencing technologies applied to DNA methylation analysis, as well as in development of biosensors that represent their cheaper and faster alternatives. Most importantly, we highlight not only advantages, but also disadvantages and challenges of each method.

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