DNA methylation and its role in the trophoblast cell lineage

Tanaka, Satoshi; Nakanishi, Momo O.; Shiota, Kunio

doi:10.1387/ijdb.140053st

Cited by 13 publications

(8 citation statements)

References 94 publications

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“…DNA methylation has been the most studied epigenetic modification and is associated to gene silencing when occurring in the promoter region of genes [8]. This epigenetic mark usually occurs in CpG dinucleotides and consists in the addition of a methyl group from the S-adenosylmethionine donor (SAM) to the fifth carbon of a cytosine, originating a 5-methylcytosine (5-mC) [9,10]. The enzymes that catalyze DNA methylation are well characterized and are designated DNA methyltransferases (DNMTs).…”

Section: Introductionmentioning

confidence: 99%

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Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses

et al. 2019

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Epigenetic mechanisms such as genomic imprinting have a fundamental role in embryo and fetal development. Hence, we here studied expression levels of epigenetic modifiers and imprinted genes in cases of ididopathic spontaneous abortion (SA). Thirty-five placental samples and 35 matched fetal tissues from second trimester SA were analysed; including 16 controls (placental and fetal infections as the known cause of spontaneous abortion) and 19 idiopathic SA cases. Transcript levels of epigenetic regulators and imprinted genes were measured by qRT-PCR and methylation at imprinted genes was studied by bisulfite genomic sequencing and MS-MLPA. Global DNA hydroxymethylation (5-hmC) levels were measured by an ELISA-based assay. We observed an upregulation of TET2 and TET3 in placental samples from idiopathic SA cases; however, no significant difference in global 5-hmC levels was observed. On the contrary, in fetal tissues, TET3 was markedly downregulated in idiopathic SA, showing an opposite trend to that observed in placental tissue. IGF2 and CDKN1C were upregulated and MEST downregulated in placentas from idiopathic SA cases; concordantly, IGF2 was also upregulated in fetal tissues from idiopathic SA cases. Although not reaching statistical significance, an increase in methylation levels of MEST, KvDMR1 and H19 DMRs was observed in idiopathic SA cases, concordantly with the observed changes in expression. Our study reveals, for the first time, deregulation of epigenetic modifiers and imprinted genes in both placental and fetal tissues from idiopathic SA cases in the second trimester of pregnancy, indicating a critical role during pregnancy.

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Section: Introductionmentioning

confidence: 99%

“…The enzymes that catalyze DNA methylation are well characterized and are designated DNA methyltransferases (DNMTs). Within this family, three enzymatically active types are identified, the maintenance methyltransferase DNMT1 and the de novo methyltransferases, DNMT3A and DNMT3B [9,11].…”

Section: Introductionmentioning

confidence: 99%

Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses

et al. 2019

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“…In contrast, H4 neither displays sequence divergence nor has any identified variants 14 , 15 . High-order chromatin organization in mammals is modulated by several epigenetic mechanisms, including DNA methylation and histone post-translational modifications 18 – 20 . Since there is a wide variety of histones, chromatin structure might change by changing the combination of histones.…”

Section: Introductionmentioning

confidence: 99%

Nucleosomes of polyploid trophoblast giant cells mostly consist of histone variants and form a loose chromatin structure

Hayakawa

Terada

Takahashi

et al. 2018

Sci Rep

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Trophoblast giant cells (TGCs) are one of the cell types that form the placenta and play multiple essential roles in maintaining pregnancy in rodents. TGCs have large, polyploid nuclei resulting from endoreduplication. While previous studies have shown distinct gene expression profiles of TGCs, their chromatin structure remains largely unknown. An appropriate combination of canonical and non-canonical histones, also known as histone variants, allows each cell to exert its cell type-specific functions. Here, we aimed to reveal the dynamics of histone usage and chromatin structure during the differentiation of trophoblast stem cells (TSCs) into TGCs. Although the expression of most genes encoding canonical histones was downregulated, the expression of a few genes encoding histone variants such as H2AX, H2AZ, and H3.3 was maintained at a relatively high level in TGCs. Both the micrococcal nuclease digestion assay and nucleosome stability assay using a microfluidic device indicated that chromatin became increasingly loose as TSCs differentiated. Combinatorial experiments involving H3.3-knockdown and -overexpression demonstrated that variant H3.3 resulted in the formation of loose nucleosomes in TGCs. In conclusion, our study revealed that TGCs possessed loose nucleosomes owing to alterations in their histone composition during differentiation.

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“…Trophoblast methylation/demethylation is a major mechanism for differentiation and development. Although it is generally accepted that the methylation process is inhibitory during preimplantation embryonic development, it has been recently shown that active demethylation processes occur after implantation (10,11). Deregulation of the demethylation process could cause pregnancy-related diseases like PE.…”

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confidence: 99%

Ten-eleven translocation 2 demethylates the MMP9 promoter, and its down-regulation in preeclampsia impairs trophoblast migration and invasion

Shen

et al. 2018

Journal of Biological Chemistry

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Preeclampsia is the most common clinical disorder in pregnancy and might result from disordered uterine environments caused by epigenetic modifications, including deregulation of DNA methylation/demethylation. Recent research has indicated that 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine (5mC) via oxidation by ten-eleven translocation (TET) enzymes, is involved in DNA methylation-related plasticity. Here, we report that TET2 expression and 5hmC abundance are significantly altered in the placentas from preeclampsia patients. shRNA-mediated TET2 knockdown (shTET2) reduced trophoblast migration and invasion when cultured in Matrigel. Both real-time PCR of matrix metalloproteinase (MMP)-related transcripts and a human angiogenesis antibody array indicated that TET2 knockdown in trophoblasts inhibits the expression of MMP transcript, of which MMP9 represented one of the most significant TET2 downstream targets. Using an established shTET2 HTR-8/SVneo cell model, we further confirmed alterations of 5hmC levels and MMP9 expression at both mRNA and protein levels. In particular, we found that TET2 bound to and removed 5mC modifications at the promoter region. Interestingly, in TET2 knockdown cells, both MMP9 expression and the compromised trophoblast phenotype could be rescued by vitamin C, an activator of TET enzyme activity. Finally, TET2 expression correlated with MMP9 levels in placenta samples from the preeclampsia patients, indicating that TET2 deregulation is critically involved in the pathogenesis of preeclampsia through down-regulation of MMP9 expression. Our findings highlight a critical role of TET2 in regulating trophoblast cell migration through demethylation at the promoter, and suggest that down-regulation of the TET2-MMP9-mediated pathway contributes to preeclampsia pathogenesis.

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DNA methylation and its role in the trophoblast cell lineage

Cited by 13 publications

References 94 publications

Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses

Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses

Nucleosomes of polyploid trophoblast giant cells mostly consist of histone variants and form a loose chromatin structure

Ten-eleven translocation 2 demethylates the MMP9 promoter, and its down-regulation in preeclampsia impairs trophoblast migration and invasion

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