Cell division drives DNA methylation loss in late-replicating domains in primary human cells [methylation array]
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ABSTRACT:
PROVIDER: PRJNA810865 | ENA |
REPOSITORIES: ENA
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Project description:We present the first experimental evidence that loss of DNA methylation at late-replicating regions, widely documented in aging and cancer, is directly driven by cell division. DNA hypomethylation, particularly at low-density CpGs in A:T-rich, partially methylated domains (PMD solo-WCGWs), tracks cumulative population doublings in primary cell culture. Cell cycle deceleration or full arrest resulted in a proportional decrease in the rate of DNA methylation loss. Lower culture oxygen conditions resulted in a slowed rate of methylation loss, suggesting that these CpGs may also be vulnerable to methylation loss during unscheduled, repair-associated methylation maintenance as well as scheduled, replication-associated methylation maintenance. By studying this methylation context in immortalized primary cells, we identified genomic and epigenomic features that are resistant or more susceptible to methylation loss. Finally, we leveraged this extensive DNA methylation dataset to develop a refined metric for the relative cumulative mitotic histories of human cells. These RNA-sequencing data accompany the larger DNA methylation dataset.
2022-07-25 | GSE197512 | GEO
Project description:Cell division drives DNA methylation loss in late-replicating domains in primary human cells
| PRJNA810863 | ENA
Project description:We present the first experimental evidence that loss of DNA methylation at late-replicating regions, widely documented in aging and cancer, is directly driven by cell division. DNA hypomethylation, particularly at low-density CpGs in A:T-rich, partially methylated domains (PMD solo-WCGWs), tracks cumulative population doublings in primary cell culture. Cell cycle deceleration or full arrest resulted in a proportional decrease in the rate of DNA methylation loss. Lower culture oxygen conditions resulted in a slowed rate of methylation loss, suggesting that these CpGs may also be vulnerable to methylation loss during unscheduled, repair-associated methylation maintenance as well as scheduled, replication-associated methylation maintenance. By studying this methylation context in immortalized primary cells, we identified genomic and epigenomic features that are resistant or more susceptible to methylation loss. Finally, we leveraged this extensive DNA methylation dataset to develop a refined metric for the relative cumulative mitotic histories of human cells. These RNA-sequencing data accompany the larger DNA methylation dataset.
2022-07-25 | GSE197471 | GEO
Project description:Cell division drives DNA methylation loss in late-replicating domains in primary human cells [RNA-seq]
| PRJNA810446 | ENA
Project description:The methylation state of lysine 20 on histone H4 (H4K20) has been linked to cell cycle progression, Origin Recognition Complex (ORC) binding, and replication origin regulation. Monomethylation of H4K20 (H4K20me1) is mediated by the cell cycle-regulated histone methyltransferase PR-Set7, which is essential for genome integrity and cell cycle progression. PR-Set7 depletion in mammalian cells results in defective S-phase progression and the accumulation of DNA damage, which could be partially attributed to a defect in pre-Replication Complex (pre-RC) formation and origin activity. However, these studies were limited to a handful of mammalian origins, and it remains unclear how PR-Set7 and H4K20 methylation impact the replication program on a genomic scale. Using Drosophila Kc167 cells, we employed genetic, cytological, and genomic approaches to better understand the role of PR-Set7 and H4K20 methylation in regulating DNA replication and governing genome stability. We find that depletion of Drosophila PR-Set7 and loss of H4K20me1 result in the accumulation of DNA damage and an ATR-dependent cell cycle arrest. The cell cycle arrest occurs during the second S-phase following loss of PR-Set7 activity, suggesting that accumulation of nascent H4K20 is recalcitrant to the DNA replication program. Deregulation of H4K20 methylation had no impact on origin activation throughout the genome; instead, we found that the DNA damage marker, phosphorylated H2A.v (γ-H2A.v), accumulated specifically in late replicating domains in the absence of PR-Set7. This suggests that the molecular basis for the cell cycle arrest and accumulation of DNA damage resulting from loss of PR-Set7 is stochastic fork collapse within late replicating domains.
2015-10-08 | GSE73668 | GEO
Project description:DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed partially methylated domains (PMDs). We profiled 39 diverse primary tumors and 8 matched adjacent tissues using whole-genome bisulfite sequencing (WGBS) and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context ('solo-WCGWs') identified previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increased with age, beginning during fetal development, and appeared to track the accumulation of cell divisions. In cancer, PMD hypomethylation depth correlated with somatic mutation density and cell cycle gene expression, consistent with its reflection of mitotic history and suggesting its application as a mitotic clock. We propose that late replication leads to lifelong progressive methylation loss, which acts as a biomarker for cellular aging and which may contribute to oncogenesis.
| S-EPMC5893360 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE27518: LATE-REPLICATING HETEROCHROMATIN IS CHARACTERISED BY DECREASED CYTOSINE METHYLATION IN THE HUMAN GENOME (expression) GSE27537: LATE-REPLICATING HETEROCHROMATIN IS CHARACTERISED BY DECREASED CYTOSINE METHYLATION IN THE HUMAN GENOME (HELP assay) Refer to individual Series
2011-08-05 | E-GEOD-27538 | biostudies-arrayexpress
Project description:Mitotic cell division increases tumour mutation burden and copy number load with a positive and inverse correlation, respectively, with the clinical benefit of immunotherapy. Markers of cell division correlate also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation as a combination regimens for precision immunotherapy.
2019-07-31 | GSE119144 | GEO
Project description:Heterochromatin is believed to be associated with increased levels of cytosine methylation. With the recent availability of genome-wide, high-resolution molecular data reflecting cytosine methylation or heterochromatic organization, such relationships can be explored systematically. As a well-defined surrogate for heterochromatin, we tested the relationship between DNA replication timing and cytosine methylation in two human cell types, unexpectedly finding that the later-replicating, more heterochromatic regions to be less methylated than early-replicating regions. When we integrated gene expression data into the study, we found that regions of increased gene expression were earlier replicating, as previously identified, and that transcription-targeted cytosine methylation (TTCM) in gene bodies accounts for the positive correlation with early replication. A Self-Organising Map (SOM) approach was able to identify genomic regions with early replication and increased methylation but lacking annotated transcripts, which would have been missed in simple two variable analyses and may encode unrecognized intergenic transcripts. We conclude that the relationship of cytosine methylation with heterochromatin is not simple, and depends on whether the genomic context is tandemly-repetitive sequences often found near centromeres, which are known to be heterochromatic and methylated, or the remaining majority of the genome, where cytosine methylation is targeted preferentially to the transcriptionally-active, euchromatic compartment of the genome. comparison of human fibroblast and GM06690
2011-08-05 | E-GEOD-27518 | biostudies-arrayexpress
Project description:Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy.
2019-08-02 | GSE135222 | GEO