Sequence features of retrotransposons allow for epigenetic variability

Transposable elements (TEs) are mobile genetic elements that make up a large fraction of mammalian genomes. While select TEs have been co-opted in host genomes to have function, the majority of these elements are epigenetically silenced by DNA methylation in somatic cells. However, some TEs in mice, including the Intracisternal A-particle (IAP) subfamily of retrotransposons, have been shown to display interindividual variation in DNA methylation. Recent work has revealed that IAP sequence differences and strain-specific KRAB zinc finger proteins (KZFPs) may influence the methylation state of these IAPs. However, the mechanisms underlying the establishment and maintenance of interindividual variability in DNA methylation still remain unclear. Here we report that sequence content and genomic context influence the likelihood that IAPs become variably methylated. IAPs that differ from consensus IAP sequences have altered KZFP recruitment that can lead to decreased KAP1 recruitment when in proximity of constitutively expressed genes. These variably methylated loci have a high CpG density, similar to CpG islands, and can be bound by ZF-CxxC proteins, providing a potential mechanism to maintain this permissive chromatin environment and protect from DNA methylation. These observations indicate that variably methylated IAPs escape silencing through both attenuation of KZFP binding and recognition by ZF-CxxC proteins to maintain a hypomethylated state.

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Mechanisms regulating interindividual epigenetic variability at transposable elements

10.1101/2021.06.01.446659 ◽

2021 ◽

Author(s):

Kevin R Costello ◽

Amy Leung ◽

Candi Trac ◽

Michael Lee ◽

Mudasar Basam ◽

...

Keyword(s):

Dna Methylation ◽

Transposable Elements ◽

Mouse Genome ◽

Large Fraction ◽

Sequence Divergence ◽

Interindividual Variation ◽

Epigenetic Variability ◽

Genomic Context ◽

Mammalian Genomes ◽

Intracisternal A Particle

Transposable elements (TEs) are mobile genetic elements that make up a large fraction of mammalian genomes. While select TEs have been co-opted in host genomes to have function, the vast majority of these elements are epigenetically silenced in somatic cells. However, some TEs in the mouse genome, including the Intracisternal A-particle (IAP) subfamily of retrotransposons, have been shown to display interindividual variation in DNA methylation. While recent work has identified that IAP sequence differences and strain-specific KRAB zinc finger proteins (KZFPs) may influence the methylation state of these IAPs, the mechanisms underlying the establishment and maintenance of interindividual variability in DNA methylation still remain unclear. Here we report that sequence divergence and genomic context influence the likelihood that IAPs become variably methylated. IAPs that have diverged from the consensus IAP sequence have altered KZFP recruitment that can lead to decreased KAP1 recruitment when in a euchromatic environment. These variably methylated loci have a high CpG density and are bound by ZF-CxxC proteins, providing a potential mechanism to maintain this permissive chromatin environment and protect from DNA methylation. These observations indicate that variably methylated IAPs escape silencing through both attenuation of KZFP binding and recognition by CxxC-containing proteins to maintain a hypomethylated state.

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Characteristics of DNA methylation and gene expression in regulatory features on the Infinium 450k Beadchip

10.1101/032862 ◽

2015 ◽

Cited By ~ 5

Author(s):

David Martino ◽

Richard Saffery

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Cpg Island ◽

Association Studies ◽

Cpg Islands ◽

Transcriptional Unit ◽

Gene Body ◽

Genomic Context ◽

Methylation Array ◽

The Relationship

Understanding the relationship between variations in DNA methylation and gene expression has been challenging. Evidence suggests the function of DNA methylation may vary with genomic context, and few consistent rules linking methylation to expression have been noted. For array-based studies, the content of current DNA methylation array platforms provide broad coverage of the genome but target only a fraction of the potentially methylated CG dinucleotides. A better understanding of the interplay between DNA methylation and gene expression is beneficial for users of these platforms, and may aid with candidate prioritization in epigenome-wide association studies (EWAS). To address this we examined the relationship between DNA methylation levels and gene expression in primary T-lymphocytes at discreet genomic regions around the transcriptional unit (Promoters, gene body, untranslated regions) and at CpG island-associated regions (islands, shores and shelves), stratifying by high and low expressed genes. As anticipated we found evidence that DNA methylation at CpG sites near promoter regions are tightly correlated with gene expression in both the stably expressed and developmentally regulated genes, however this is dependent on CpG density. DNA methylation within the gene body was not consistently associated with changes in gene expression. CpG islands and island shores exhibited strong correlations with gene expression, but this was not true for island shelves. We found these relationships were generally preserved at both dynamic and steady state genes, with some notable exceptions. In combination these insights may be useful for prioritising candidates identified in epigenome-wide association studies for subsequent functional studies.

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Transcription of intragenic CpG islands influences spatiotemporal host gene pre-mRNA processing

10.1101/2020.05.04.076729 ◽

2020 ◽

Author(s):

Samuele M Amante ◽

Bertille Montibus ◽

Michael Cowley ◽

Nikolaos Barkas ◽

Jessica Setiadi ◽

...

Keyword(s):

Dna Methylation ◽

Expression Patterns ◽

Cpg Islands ◽

Alternative Polyadenylation ◽

Mrna Processing ◽

Host Gene ◽

Independent Manner ◽

Mammalian Genomes ◽

Development And Differentiation ◽

Host Genes

ABSTRACTAlternative splicing (AS) and alternative polyadenylation (APA) generate diverse transcripts in mammalian genomes during development and differentiation. Epigenetic factors such as trimethylation of histone H3 lysine 36 (H3K36me3) and DNA methylation play a role in generating transcriptome diversity. Intragenic CpG islands (iCGIs) and their corresponding host genes exhibit dynamic epigenetic and gene expression patterns during development and between different tissues. We hypothesise that iCGI-associated H3K36me3, DNA methylation and transcription can influence host gene AS and/or APA. We investigate H3K36me3 and find that this histone mark is not a major regulator of AS or APA in our model system. Genomewide, we identify over 4000 host genes that harbour an iCGI in the mammalian genome, including both previously annotated and novel iCGI/host gene pairs. The transcriptional activity of these iCGIs is tissue- and developmental stage-specific and, for the first time, we demonstrate that the premature termination of host gene transcripts upstream of iCGIs is closely correlated with the level of iCGI transcription in a DNA-methylation independent manner. These studies suggest that iCGI transcription, rather than H3K36me3 or DNA methylation, interfere with host gene transcription and pre-mRNA processing genomewide and contributes to the spatiotemporal diversification of both the transcriptome and proteome.

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Targets and genomic constraints of ectopic Dnmt3b expression

eLife ◽

10.7554/elife.40757 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 10

Author(s):

Yingying Zhang ◽

Jocelyn Charlton ◽

Rahul Karnik ◽

Isabel Beerman ◽

Zachary D Smith ◽

...

Keyword(s):

Dna Methylation ◽

Dna Methyltransferase ◽

De Novo ◽

Cpg Island ◽

Cpg Islands ◽

Cell Types ◽

Aberrant Methylation ◽

Genome Wide Data ◽

Mammalian Genomes ◽

Different Cell Types

DNA methylation plays an essential role in mammalian genomes and expression of the responsible enzymes is tightly controlled. Deregulation of the de novo DNA methyltransferase DNMT3B is frequently observed across cancer types, yet little is known about its ectopic genomic targets. Here, we used an inducible transgenic mouse model to delineate rules for abnormal DNMT3B targeting, as well as the constraints of its activity across different cell types. Our results explain the preferential susceptibility of certain CpG islands to aberrant methylation and point to transcriptional state and the associated chromatin landscape as the strongest predictors. Although DNA methylation and H3K27me3 are usually non-overlapping at CpG islands, H3K27me3 can transiently co-occur with DNMT3B-induced DNA methylation. Our genome-wide data combined with ultra-deep locus-specific bisulfite sequencing suggest a distributive activity of ectopically expressed Dnmt3b that leads to discordant CpG island hypermethylation and provides new insights for interpreting the cancer methylome.

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Transcription of intragenic CpG islands influences spatiotemporal host gene pre-mRNA processing

Nucleic Acids Research ◽

10.1093/nar/gkaa556 ◽

2020 ◽

Vol 48 (15) ◽

pp. 8349-8359

Author(s):

Samuele M Amante ◽

Bertille Montibus ◽

Michael Cowley ◽

Nikolaos Barkas ◽

Jessica Setiadi ◽

...

Keyword(s):

Dna Methylation ◽

Expression Patterns ◽

Cpg Islands ◽

Alternative Polyadenylation ◽

Mrna Processing ◽

Host Gene ◽

Independent Manner ◽

Mammalian Genomes ◽

Development And Differentiation ◽

Host Genes

Abstract Alternative splicing (AS) and alternative polyadenylation (APA) generate diverse transcripts in mammalian genomes during development and differentiation. Epigenetic marks such as trimethylation of histone H3 lysine 36 (H3K36me3) and DNA methylation play a role in generating transcriptome diversity. Intragenic CpG islands (iCGIs) and their corresponding host genes exhibit dynamic epigenetic and gene expression patterns during development and between different tissues. We hypothesise that iCGI-associated H3K36me3, DNA methylation and transcription can influence host gene AS and/or APA. We investigate H3K36me3 and find that this histone mark is not a major regulator of AS or APA in our model system. Genomewide, we identify over 4000 host genes that harbour an iCGI in the mammalian genome, including both previously annotated and novel iCGI/host gene pairs. The transcriptional activity of these iCGIs is tissue- and developmental stage-specific and, for the first time, we demonstrate that the premature termination of host gene transcripts upstream of iCGIs is closely correlated with the level of iCGI transcription in a DNA-methylation independent manner. These studies suggest that iCGI transcription, rather than H3K36me3 or DNA methylation, interfere with host gene transcription and pre-mRNA processing genomewide and contributes to the spatiotemporal diversification of both the transcriptome and proteome.

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Data Mining Technique Applied To DNA Sequencing

International Research Journal of Management IT and Social Sciences ◽

10.21744/irjmis.v2i7.70 ◽

2015 ◽

Vol 2 (7) ◽

pp. 18

Author(s):

R. Jamuna

Keyword(s):

Data Mining ◽

Dna Methylation ◽

Markov Chain ◽

Human Genome ◽

Transition Probabilities ◽

Markov Chain Model ◽

Effective Means ◽

Cpg Islands ◽

Chain Model ◽

The Given

CpG islands (CGIs) play a vital role in genome analysis as genomic markers. Identification of the CpG pair has contributed not only to the prediction of promoters but also to the understanding of the epigenetic causes of cancer. In the human genome [1] wherever the dinucleotides CG occurs the C nucleotide (cytosine) undergoes chemical modifications. There is a relatively high probability of this modification that mutates C into a T. For biologically important reasons the mutation modification process is suppressed in short stretches of the genome, such as ‘start’ regions. In these regions [2] predominant CpG dinucleotides are found than elsewhere. Such regions are called CpG islands. DNA methylation is an effective means by which gene expression is silenced. In normal cells, DNA methylation functions to prevent the expression of imprinted and inactive X chromosome genes. In cancerous cells, DNA methylation inactivates tumor-suppressor genes, as well as DNA repair genes, can disrupt cell-cycle regulation. The most current methods for identifying CGIs suffered from various limitations and involved a lot of human interventions. This paper gives an easy searching technique with data mining of Markov Chain in genes. Markov chain model has been applied to study the probability of occurrence of C-G pair in the given gene sequence. Maximum Likelihood estimators for the transition probabilities for each model and analgously for the model has been developed and log odds ratio that is calculated estimates the presence or absence of CpG is lands in the given gene which brings in many facts for the cancer detection in human genome.

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Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at PRC1-targeted CpG islands

Nature Genetics ◽

10.1038/s41588-021-00856-5 ◽

2021 ◽

Author(s):

Daniel N. Weinberg ◽

Phillip Rosenbaum ◽

Xiao Chen ◽

Douglas Barrows ◽

Cynthia Horth ◽

...

Keyword(s):

Dna Methylation ◽

De Novo ◽

Cpg Islands

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DNA Methylation of Human Choline Kinase Alpha Promoter-Associated CpG Islands in MCF-7 Cells

Genes ◽

10.3390/genes12060853 ◽

2021 ◽

Vol 12 (6) ◽

pp. 853

Author(s):

Siti Aisyah Faten Mohamed Sa’dom ◽

Sweta Raikundalia ◽

Shaharum Shamsuddin ◽

Wei Cun See Too ◽

Ling Ling Few

Keyword(s):

Dna Methylation ◽

Transcription Factor ◽

Binding Site ◽

Promoter Activity ◽

Cytosine Methylation ◽

Cpg Island ◽

Cpg Islands ◽

Site Directed Mutagenesis ◽

Choline Kinase ◽

Mcf 7

Choline kinase (CK) is the enzyme catalyzing the first reaction in CDP-choline pathway for the biosynthesis of phosphatidylcholine. Higher expression of the α isozyme of CK has been implicated in carcinogenesis, and inhibition or downregulation of CKα (CHKA) is a promising anticancer approach. This study aimed to investigate the regulation of CKα expression by DNA methylation of the CpG islands found on the promoter of this gene in MCF-7 cells. Four CpG islands have been predicted in the 2000 bp promoter region of ckα (chka) gene. Six CpG island deletion mutants were constructed using PCR site-directed mutagenesis method and cloned into pGL4.10 vectors for promoter activity assays. Deletion of CpG4C region located between –225 and –56 significantly increased the promoter activity by 4-fold, indicating the presence of important repressive transcription factor binding site. The promoter activity of methylated full-length promoter was significantly lower than the methylated CpG4C deletion mutant by 16-fold. The results show that DNA methylation of CpG4C promotes the binding of the transcription factor that suppresses the promoter activity. Electrophoretic mobility shift assay analysis showed that cytosine methylation at MZF1 binding site in CpG4C increased the binding of putative MZF1 in nuclear extract. In conclusion, the results suggest that DNA methylation decreased the promoter activity by promoting the binding of putative MZF1 transcription factor at CpG4C region of the ckα gene promoter.

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PGC7 suppresses TET3 for protecting DNA methylation

Nucleic Acids Research ◽

10.1093/nar/gkt1261 ◽

2013 ◽

Vol 42 (5) ◽

pp. 2893-2905 ◽

Cited By ~ 39

Author(s):

Chunjing Bian ◽

Xiaochun Yu

Keyword(s):

Dna Methylation ◽

Molecular Mechanism ◽

Biological Process ◽

Cpg Islands ◽

Binding Motifs ◽

Genome Wide Analysis ◽

Dna Motif ◽

Genome Wide

Abstract Ten-eleven translocation (TET) family enzymes convert 5-methylcytosine to 5-hydroxylmethylcytosine. However, the molecular mechanism that regulates this biological process is not clear. Here, we show the evidence that PGC7 (also known as Dppa3 or Stella) interacts with TET2 and TET3 both in vitro and in vivo to suppress the enzymatic activity of TET2 and TET3. Moreover, lacking PGC7 induces the loss of DNA methylation at imprinting loci. Genome-wide analysis of PGC7 reveals a consensus DNA motif that is recognized by PGC7. The CpG islands surrounding the PGC7-binding motifs are hypermethylated. Taken together, our study demonstrates a molecular mechanism by which PGC7 protects DNA methylation from TET family enzyme-dependent oxidation.

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Pilot study of DNA methylation in the pathogenesis of chronic rhinosinusitis with nasal polyps

Rhinology Journal ◽

10.4193/rhino14.086 ◽

2015 ◽

Vol 53 (4) ◽

pp. 345-352

Author(s):

Y.B. Zheng ◽

Y. Zhao ◽

L.Y. Yue ◽

P. Lin ◽

Y.F. Liu ◽

...

Keyword(s):

Dna Methylation ◽

Polymerase Chain Reaction ◽

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Cpg Islands ◽

Inferior Turbinate ◽

Control Group ◽

Chain Reaction ◽

Bisulphite Sequencing ◽

Polymerase Chain

Background: DNA methylation has been implicated in the pathogenesis of allergy and atopy. This study aimed to identify whether DNA methylation also plays an important role in the pathogenesis of nasal polyps (NP). Methodology: NP tissues were obtained from 32 patients with chronic rhinosinusitis with bilateral NP. Biopsies of inferior turbinate mucosa (ITM) were taken from 18 patients who underwent rhinoseptoplasty (control group). The methylated genes, which were detected by DNA methylation microarray, were validated by methylation-specific polymerase chain reaction, bisulphite sequencing, real-time polymerase chain reaction and immunohistochemistry. Results: DNA methylation microarray identified 8,008 CpG islands in 2,848 genes. One hundred and ninety-eight genes were found to have a methylated signal in the promoter region in NP samples compared with ITM samples. The four top genes that changed, COL18A1, EP300, GNAS and SMURF1, were selected for further study. The methylation frequency of COL18A1 was significantly higher in NP samples than in ITM samples. Conclusions: DNA methylation might play an important role in the pathogenesis of NP. Promoter methylation of COL18A1 was found to be significantly increased in NP tissues, further studies are necessary to confirm the significance of these epigenetic factors in the mechanisms underlying the development or persistence of NP.

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