DNA damage and Repair Modify DNA methylation and Chromatin Domain of the Targeted Locus: Mechanism of allele methylation polymorphism

Russo, G.; Landi, Rosaria; Pezone, Antonio; Morano, Annalisa; Zuchegna, Candida; Romano, Antonella; Muller, Mark T.; Gottesman, Max E.; Porcellini, Antonio; Avvedimento, Enrico V.

doi:10.1038/srep33222

Cited by 69 publications

(61 citation statements)

References 35 publications

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“…As DNA damage has been proposed as a mechanism for DNA methylation changes (Russo et al, 2016), we assessed DNA damage in the samples analyzed in the current study. We used the alkaline comet assay to measure sperm DNA damage and, as reported previously, we found marginally increased DNA damage in sperm from men who smoke compared with controls (p = 0.05).…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoking significantly alters sperm DNA methylation patterns

et al. 2017

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Numerous health consequences of tobacco smoke exposure have been characterized, and smoking’s effects on traditional measures of male fertility are well described. However, a growing body of data indicates that pre-conception paternal smoking also confers increased risk for a number of morbidities on offspring. The mechanism for this increased risk has not been elucidated, but it is likely mediated, at least in part, through epigenetic modifications transmitted through sperm. In this study, we investigated the impact of cigarette smoke exposure on sperm DNA methylation patterns in 78 men who smoke and 78 never-smokers using the Infinium HumanMethylation450 beadchip. We investigated two models of DNA methylation alterations: (1) consistently altered methylation at specific CpGs or within specific genomic regions and (2) stochastic DNA methylation alterations manifest as increased variability in genome-wide methylation patterns in men who smoke. We identified 141 significantly differentially methylated CpGs associated with smoking. In addition, we identified a trend toward increased variance in methylation patterns genome-wide in sperm DNA from men who smoke compared with never-smokers. These findings of widespread DNA methylation alterations are consistent with the broad range of offspring heath disparities associated with pre-conception paternal smoke exposure and warrant further investigation to identify the specific mechanism by which sperm DNA methylation perturbation confers risk to offspring health and whether these changes can be transmitted to offspring and transgenerationally.

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Section: Discussionmentioning

confidence: 99%

Cigarette smoking significantly alters sperm DNA methylation patterns

et al. 2017

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“…Depending on the localization and density of the methylation sites in each cell clone, the expression of the repaired gene progressively changes [11][12][13][14]. Thus, methylated clones will dominate over others if silencing of the gene produces a strong positive selection.…”

Section: Introductionmentioning

confidence: 99%

Methylation of the Suppressor Gene p16INK4a: Mechanism and Consequences

et al. 2020

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Tumor suppressor genes in the CDKN2A/B locus (p15INK4b, p16INK4a, and p14ARF) function as biological barriers to transformation and are the most frequently silenced or deleted genes in human cancers. This gene silencing frequently occurs due to DNA methylation of the promoter regions, although the underlying mechanism is currently unknown. We present evidence that methylation of p16INK4a promoter is associated with DNA damage caused by interference between transcription and replication processes. Inhibition of replication or transcription significantly reduces the DNA damage and CpGs methylation of the p16INK4a promoter. We conclude that de novo methylation of the promoter regions is dependent on local DNA damage. DNA methylation reduces the expression of p16INK4a and ultimately removes this barrier to oncogene-induced senescence.

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“…An intriguing possibility lies in the targeted DSB induction. Studies in mammalian cells have shown that targeted DNA methylation occurs upon homology-mediated repair of induced DSBs, resulting in variable gene expression among cells (Cuozzo et al, 2007;Morano et al, 2014;Russo et al, 2016). This is facilitated through recruitment of DNA methyltransferases and histone-modifying enzymes at the DSB during HR.…”

Section: Discussionmentioning

confidence: 99%

Impact of differential DNA methylation on transgene expression in cotton (Gossypium hirsutum L.) events generated by targeted sequence insertion

Verkest¹,

Bourout²,

Debaveye³

et al. 2019

Plant Biotechnology Journal

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Summary Targeted Genome Optimization ( TGO ) using site‐specific nucleases to introduce a DNA double‐strand break ( DSB ) at a specific target locus has broadened the options available to breeders for generation and combination of multiple traits. The use of targeted DNA cleavage in combination with homologous recombination ( HR )‐mediated repair, enabled the precise targeted insertion of additional trait genes (2m epsps, hppd, axmi115 ) at a pre‐existing transgenic locus in cotton. Here we describe the expression and epigenome analyses of cotton Targeted Sequence Insertion ( TSI ) events over generations. In a subset of events, we observed variability in the level of transgene ( hppd , axmi115 ) expression between independent but genetically identical TSI events. Transgene expression could also be differential within single events and variable over generations. This expression variability and silencing occurred independently of the transgene sequence and could be attributed to DNA methylation that was further linked to different DNA methylation mechanisms. The trigger(s) of transgene DNA methylation remains elusive but we hypothesize that targeted DSB induction and repair could be a potential trigger for DNA methylation.

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DNA damage and Repair Modify DNA methylation and Chromatin Domain of the Targeted Locus: Mechanism of allele methylation polymorphism

Cited by 69 publications

References 35 publications

Cigarette smoking significantly alters sperm DNA methylation patterns

Cigarette smoking significantly alters sperm DNA methylation patterns

Methylation of the Suppressor Gene p16INK4a: Mechanism and Consequences

Impact of differential DNA methylation on transgene expression in cotton (Gossypium hirsutum L.) events generated by targeted sequence insertion

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