Strand-specific CpG hemimethylation, a novel epigenetic modification functional for genomic imprinting

Patiño-Parrado, Iris; Gómez-Jiménez, Álvaro; López-Sánchez, Noelia; Frade, José Marı́a

doi:10.1093/nar/gkx518

Cited by 11 publications

(7 citation statements)

References 40 publications

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“…S4C). Notably, the imprinting region of GNAS also exhibited hemimethylation, which is in line with recent studies on imprinting regions (Guntrum et al 2017;Patino-Parrado et al 2017). The stable hemimethylation at individual CpGs of senescence-associated regions and on specific DNA strands argues against the possibility that this effect is caused by loss of DNAm during cell divisionit might rather be evoked by altered states of higher order chromatin conformation (Xu and Corces 2018).…”

Section: Senescence-associated Dna Methylation Is Often Strand-specificsupporting

confidence: 90%

“…DNAm maintenance is particularly mediated by DNA methyltransferase 1 (DNMT1) but also by the de novo methyltransferases DNMT3A and DNMT3B (Jones and Liang 2009). Using hairpinbisulfite PCR (Laird et al 2004) several studies have demonstrated that, despite the general preference for concordant DNA methylation on both strands, some particular sites are specifically methylated on only one strand (Arand et al 2015;Choi et al 2017;Patino-Parrado et al 2017). More recently, it was shown that such hemimethylation is stably inherited over several passages and that hemimethylated sites are associated with CCCTC-binding factor (CTCF)/cohesin binding sites.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic drift during long-term culture of cells in vitro

Franzen

Georgomanolis

Selich

et al. 2018

Preprint

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Replicative senescence of cells in culture is associated with highly reproducible DNA methylation (DNAm) changes at specific sites in the genome. Thus far, it is largely unclear if these epigenetic modifications are directly regulated, or if they are randomly evoked by other chromatin changes during long-term culture.We have identified CG dinucleotides (CpGs) that become continuously hyper-or hypomethylated in the course of culture expansion of mesenchymal stem cells (MSCs) and other cell types. These modifications provide a biomarker for replicative senescence and correlate with the number of passages in vitro. During reprogramming into induced pluripotent stem cells (iPSCs) senescence-associated DNAm is reversed simultaneously with pluripotency-associated DNAm changes. Bisulfite barcoded amplicon sequencing (BBA-seq) demonstrated that upon passaging the DNAm patterns of neighboring CpGs become more complex without evidence of continuous pattern development. Notably, BBA-seq of hairpin-linked DNA molecules demonstrated that many CpG dyads are methylated only on the forward or the reverse strand. This hemimethylation was conserved over many passages, indicating that it was not due to insufficient maintenance of DNAm patterns. Circularized chromatin conformation capture (4C) of senescence-associated CpGs revealed reproducible changes during senescence without evidence for preferential interaction between CpGs that become either hyper-or hypomethylated.Taken together, senescence-associated DNAm fluctuates stochastically at specific sites in the genome. Strand-specific DNAm and reproducible changes in 4C indicate that epigenetic modifications of these CG dyads are not regulated in a targeted manner but rather caused by passage-specific higher order chromatin conformation states.

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Section: Senescence-associated Dna Methylation Is Often Strand-specificsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Epigenetic drift during long-term culture of cells in vitro

Franzen

Georgomanolis

Selich

et al. 2018

Preprint

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“…Therefore, hemimethylation may serve as a stable epigenetic mark. In addition, recent papers show that hemimethylation is a characteristic of secondary differential methylation regions that are associated with imprinted genes [ 54 – 56 ]. That is, hemimethylation is a novel epigenetic modification functional for genomic imprinting.…”

Section: Discussionmentioning

confidence: 99%

Statistical and bioinformatic analysis of hemimethylation patterns in non-small cell lung cancer

et al. 2021

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Background DNA methylation is an epigenetic event involving the addition of a methyl-group to a cytosine-guanine base pair (i.e., CpG site). It is associated with different cancers. Our research focuses on studying non-small cell lung cancer hemimethylation, which refers to methylation occurring on only one of the two DNA strands. Many studies often assume that methylation occurs on both DNA strands at a CpG site. However, recent publications show the existence of hemimethylation and its significant impact. Therefore, it is important to identify cancer hemimethylation patterns. Methods In this paper, we use the Wilcoxon signed rank test to identify hemimethylated CpG sites based on publicly available non-small cell lung cancer methylation sequencing data. We then identify two types of hemimethylated CpG clusters, regular and polarity clusters, and genes with large numbers of hemimethylated sites. Highly hemimethylated genes are then studied for their biological interactions using available bioinformatics tools. Results In this paper, we have conducted the first-ever investigation of hemimethylation in lung cancer. Our results show that hemimethylation does exist in lung cells either as singletons or clusters. Most clusters contain only two or three CpG sites. Polarity clusters are much shorter than regular clusters and appear less frequently. The majority of clusters found in tumor samples have no overlap with clusters found in normal samples, and vice versa. Several genes that are known to be associated with cancer are hemimethylated differently between the cancerous and normal samples. Furthermore, highly hemimethylated genes exhibit many different interactions with other genes that may be associated with cancer. Hemimethylation has diverse patterns and frequencies that are comparable between normal and tumorous cells. Therefore, hemimethylation may be related to both normal and tumor cell development. Conclusions Our research has identified CpG clusters and genes that are hemimethylated in normal and lung tumor samples. Due to the potential impact of hemimethylation on gene expression and cell function, these clusters and genes may be important to advance our understanding of the development and progression of non-small cell lung cancer.

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“…In the present study, pyrosequencing was selected as it is the standard technique in cancer research, detects small differences in methylation, is suitable for heterogeneous samples and provides quantitative results ( 67 , 68 ). However, it was not possible to determine whether it provides information on allele specificity or hemi-methylation, which may differentiate de novo methylation events from maintenance factors ( 69 , 70 ).…”

Section: Discussionmentioning

confidence: 99%

Methylation status of KLF4 and HS3ST2 genes as predictors of endometrial cancer and hyperplastic endometrial lesions

et al. 2018

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Endometrial carcinoma is one of the most common tumours in developed countries. In addition to the active role of genetic factors, epigenetic changes also have an important effect. The present study analysed the methylation status of kruppel like factor 4 (KLF4) and heparan sulfate-glucosamine 3-sulfotransferase 2 (HS3ST2) genes in three endometrial tissue types for carcinoma prediction. The sample comprised 91 women with histologically-confirmed endometrial carcinoma (64.16±9.64 years old), 36 women with hyperplasia (53.39±9.64 years old) and 45 with no signs or symptoms of malignancy (48.53±11.11 years old). The CpG dinucleotide methylation levels were examined by quantitative pyrosequencing, and the discrimination accuracy of the model was calculated using the Random Forest classification algorithm of the area under the ROC curve (AUC). The mean values of KLF4 and HS3ST2 methylation indices were 23.83±11.39 and 8.52±2.57 in the control samples; 30.40±8.52 and 33.76±20.66 in hyperplasia and 34.72±10.79 and 34.49±18.39 in the cancerous tissues. Multinomial logistic regression indicated that the HS3ST2 CpG1 methylation status is a predictor of hyperplasia (P<0.05) and that the KLF4 CpG2 dinucleotide can predict carcinoma formation (P<0.001). The AUC value of 0.95 indicates high discrimination accuracy of the CpG nucleotides methylation status model between the controls and the two other diagnoses. The results of the present study establish the likelihood that aberrations in KLF4 and HS3ST2 gene methylation levels are important in the development of endometrial hyperplasia and carcinoma, with hyperplasia an intermediate step between healthy and tumour tissues.

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Strand-specific CpG hemimethylation, a novel epigenetic modification functional for genomic imprinting

Cited by 11 publications

References 40 publications

Epigenetic drift during long-term culture of cells in vitro

Epigenetic drift during long-term culture of cells in vitro

Statistical and bioinformatic analysis of hemimethylation patterns in non-small cell lung cancer

Methylation status of KLF4 and HS3ST2 genes as predictors of endometrial cancer and hyperplastic endometrial lesions

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