Establishment and Functions of DNA Methylation in the Germline

Stewart, Kathleen R.; Veselovska, Lenka; Kelsey, Gavin

doi:10.2217/epi-2016-0056

Cited by 156 publications

(108 citation statements)

References 120 publications

(130 reference statements)

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“…As we know, DNA methylation is one of the major mechanisms of the genome reprogramming. 5‐hydroxymethylcytosine (5hmC) is very important in regulation of gene expression, and it has been reported to play vital roles in spermatogenesis . In our current investigation, we found that 5hmC was decreased in the testis of male offspring in ZEA exposure groups at different time‐points (14, 21 and 56 d of age) which suggested that 5hmC was involved in the ZEA‐induced toxicity on spermatogenesis.…”

Section: Discussionmentioning

confidence: 53%

“…In the current study, we found that G9a and H3K9me2 were increased in the testis of male offspring in ZEA exposure groups at different time‐points (14, 21 and 56 d of age) which indicated that G9a and H3K9me2 were also involved in the ZEA‐induced toxicity on spermatogenesis. It has been reported that there is a unique epigenome and the epigenetic changes in the spermatozoa and epigenetic modifications happen from primordial germ cells to mature gametes . As we know, DNA methylation is one of the major mechanisms of the genome reprogramming.…”

Section: Discussionmentioning

confidence: 99%

“…The epigenetic modifications including DNA methylation, histone modifications and non-coding RNAs have been found to regulate transcription and other nuclear processes in spermatogenesis. 30 Histone modifications such as methylation and acetylation of histone tails play vital roles as epigenetic mechanisms to modify gene expression. It also was reported that the activation or repression of the gene expression by histone methylation was dependent on the position of the residue modified.…”

Section: F I G U R Ementioning

confidence: 99%

“…DNA methylation is one major mechanism for the genome reprogramming. Specific 5‐methylcytosine (5mC) and 5‐hydroxymethylcytosine (5hmC) patterns have been found to play vital roles in spermatogenesis …”

Section: Introductionmentioning

confidence: 99%

“…Specific 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) patterns have been found to play vital roles in spermatogenesis. 29,30 The pubertal stage is very important for the development of the male reproductive system, due to the fast growth of testis with spermatogonial proliferation, the expansion of meiotic and haploid germ cells, and the increase in Sertoli cells and Leydig cells. 31 Even though many studies have reported that ZEA causing serious problems in spermatogenesis and the alteration in genetic factors or hormones might be the underlying mechanisms, it is not understood that epigenetic factors may be involved in this adverse impact.…”

mentioning

confidence: 99%

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Gestational exposure to low‐dose zearalenone disrupting offspring spermatogenesis might be through epigenetic modifications

Men

Zhao

Zhang

et al. 2019

Basic Clin Pharma Tox

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Zearalenone (ZEA), a F‐2 mycotoxin produced by Fusarium, has been found to be an endocrine disruptor through oestrogen receptor signalling pathway to impair spermatogenesis. The disruption on reproductive systems by ZEA exposure might be transgenerational. In our previous report, we have found that low dose (lower than no‐observed effect level, NOEL) of ZEA impaired mouse spermatogenesis and decreased mouse semen quality. The purpose of the current investigation was to explore the impacts of low‐dose ZEA on spermatogenesis in the offspring after prenatal exposure and the underlying mechanisms. And it demonstrated that prenatal low‐dose ZEA exposure disrupted the meiosis process to inhibit the spermatogenesis in offspring and even to diminish the semen quality by the decrease in spermatozoa motility and concentration. The DNA methylation marker 5hmC was decreased, the histone methylation markers H3K9 and H3K27 were elevated, and oestrogen receptor alpha was reduced in the offspring testis after prenatal low‐dose ZEA exposure. The data suggest that the disruption in spermatogenesis by prenatal low‐dose ZEA exposure may be through the modifications on epigenetic pathways (DNA methylation and histone methylation) and the interactions with oestrogen receptor signalling pathway. Moreover, in the current study, the male offspring were indirectly exposed to low‐dose ZEA through placenta and the spermatogenesis in offspring was disrupted which suggested that the toxicity of ZEA on reproductive systems was very severe. Therefore, we strongly recommend that greater attention should be paid to this mycotoxin to minimize its adverse impact on human spermatogenesis.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Gestational exposure to low‐dose zearalenone disrupting offspring spermatogenesis might be through epigenetic modifications

Men

Zhao

Zhang

et al. 2019

Basic Clin Pharma Tox

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Genomic Imprinting at the Transcriptional Level

Brandão

Rocha

2018

Encyclopedia of Life Sciences

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Genomic imprinting is an epigenetic mechanism of gene regulation causing genes to be expressed from only one of the two parentally inherited chromosomes in mammals. Imprinted genes often cluster in large chromosomal domains and their expression is regulated by cis ‐acting imprinting control regions. These regions carry an epigenetic imprint, mostly in the form of deoxyribonucleic acid methylation, laid down during gametogenesis, when the two genomes are separated. Regulation of imprinting in these clusters is thought to be explained by competition of promoters of different genes to common enhancers or cis ‐regulation induced by long noncoding RNAs. Aberrant expression of imprinted genes leads to human pathologies characterised by mental, developmental and metabolic abnormalities. Imprinting errors are also often seen in stem cells, including induced pluripotent stem cells and affect their physiology and pluripotent potential. For these reasons, genomic imprinting remains a crucial model for understanding the epigenetic influence on transcriptional activity and repression. Key Concepts A subset of genes in the mammalian genome (<1%) known as imprinted genes are expressed exclusively from one of the two parental alleles. Imprinted genes are involved in foetal growth and placental development in the uterus, as well as brain function and metabolism in adults. Most imprinted genes are physically linked in chromosomal regions known as imprinted clusters and are coordinatively regulated. Genomic imprinting at clusters is regulated by imprinting control regions (ICRs) that acquired an imprint distinguishing the two parental alleles during gametogenesis. DNA methylation is the bona fide imprint mark at ICRs, but chromatin modifications, such as H3K27me3, also serve as an imprint mark at transient and/or placental‐specific ICRs. Methylation imprints are established in the parental germ line, resist the wave of DNA demethylation after fertilisation and are erased before resetting in the germ line according to the sex. Insulation of common enhancers by the methylated sensitive protein Ctcf explains the imprinting regulation at the Igf2/H19 region. Silencing of genes in cis by long noncoding RNAs (lncRNAs) explains the imprinting regulation of, at least, three clusters through transcription interference and recruitment of chromatin modifiers. Deregulation of genomic imprinting can cause imprinted disorders in humans, which exhibit parent of origin effects in their pattern of inheritance. Imprinting defects occur in stem cells and during somatic reprogramming into induced pluripotent stem cells (iPSCs) affecting their pluripotency and harness their potential clinical applications.

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RNautophagic regulation of DNMT3a‐dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancer

Zhu

et al. 2023

Clinical & Translational Med

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Background Energy balance has long been known to extend lifespans and inhibit carcinogenesis in multiple species by slowing age‐related epigenetic changes while the underlying mechanisms remain largely unknown. Herein, we found that starvation activated autophagy to remodel the DNA methylation profile by inhibiting DNMT3a expression. Methods Illumina Infinium MethylationEPIC BeadChip and dot blot assay were performed to quantify the global DNA methylation level. Protein−RNA interactions were validated through RNA immunoprecipitation and RNA pull‐down assay. In vitro and in vivo experiments were carried out to testify the effect of DNMT3a on chemoresistance. Results Autophagy is impaired in chemoresistance which was associated with differential DNA methylation and could be reversed by DNMT3a inhibition. Autophagy activation decreases the expression of DNMT3a mRNA, accompanied with the downregulation of chemoresistance‐related Linc00942. Knockdown of Linc00942 reduces DNMT3a expression and genome‐wide DNA methylation while Linc00942 overexpression increased DNMT3a expression and correlated hypermethylation in cancer cells and primary tumour tissues. Mechanistically, Linc00942 recruits RNA methyltransferase METTL3 to stimulate N6‐methyladenosine (m6A) deposit on DNMT3a transcripts, triggering IGF2BP3/HuR to recognize modified mRNA for reinforced stability. SQSTM1/p62 recruits Linc00942 for autophagic degradation which can be abrogated after autophagy inhibition by p62 knockdown or chloroquine treatment. Conclusions Inhibition of autophagy increases Linc00942 expression to promote chemoresistance and autophagy activation or hypomethylating agent decitabine restores chemosensitivity by reducing global DNA methylation. Overall, this study identifies a novel methylation cascade linking impaired RNautophagy to global hypermethylation in chemoresistance, and provides a rationale for repurposing decitabine to overcome chemoresistance in cancer treatment.

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Establishment and Functions of DNA Methylation in the Germline

Cited by 156 publications

References 120 publications

Gestational exposure to low‐dose zearalenone disrupting offspring spermatogenesis might be through epigenetic modifications

Gestational exposure to low‐dose zearalenone disrupting offspring spermatogenesis might be through epigenetic modifications

Genomic Imprinting at the Transcriptional Level

RNautophagic regulation of DNMT3a‐dependent DNA methylation by Linc00942 enhances chemoresistance in gastric cancer

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