Repression of FGF signaling is responsible for Dnmt3b inhibition and impaired de novo DNA methylation during early development of in vitro fertilized embryos

Fu, Wei; Yue, Yuan; Kai, Masahiro; Xi, Guangyin; Zhang, Chao; Wang, Wenjuan; An, Liguo; Tian, Jianhui

doi:10.7150/ijbs.51607

Cited by 10 publications

(8 citation statements)

References 65 publications

(110 reference statements)

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“…Our recently published study identified IVF embryos undergo impaired de novo DNA methylation during implantation and postimplantation stages. We also demonstrated that FGF signaling repression and consistent Dnmt3b inhibition could be responsible for this defect, and identified FGF signaling as the main target for correcting IVFassociated DNA methylation defects (Fu et al, 2020). This work, together with our earlier study that identified impaired X chromosome inactivation is responsible for female-biased developmental defects and skewed sex ratio (Tan et al, 2016a), highlight the importance of understanding the mechanism of IVF-associated defects for improving current in vitro culture system.…”

Section: Introductionsupporting

confidence: 64%

Vitamin C Rescues in vitro Embryonic Development by Correcting Impaired Active DNA Demethylation

Chu

Yao

et al. 2021

Front. Cell Dev. Biol.

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During preimplantation development, a wave of genome-wide DNA demethylation occurs to acquire a hypomethylated genome of the blastocyst. As an essential epigenomic event, postfertilization DNA demethylation is critical to establish full developmental potential. Despite its importance, this process is prone to be disrupted due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF), and thus leading to epigenetic errors. However, since the first case of aberrant DNA demethylation reported in IVF embryos, its underlying mechanism remains unclear and the strategy for correcting this error remains unavailable in the past decade. Thus, understanding the mechanism responsible for DNA demethylation defects, may provide a potential approach for preventing or correcting IVF-associated complications. Herein, using mouse and bovine IVF embryos as the model, we reported that ten-eleven translocation (TET)-mediated active DNA demethylation, an important contributor to the postfertilization epigenome reprogramming, was impaired throughout preimplantation development. Focusing on modulation of TET dioxygenases, we found vitamin C and α-ketoglutarate, the well-established important co-factors for stimulating TET enzymatic activity, were synthesized in both embryos and the oviduct during preimplantation development. Accordingly, impaired active DNA demethylation can be corrected by incubation of IVF embryos with vitamin C, and thus improving their lineage differentiation and developmental potential. Together, our data not only provides a promising approach for preventing or correcting IVF-associated epigenetic errors, but also highlights the critical role of small molecules or metabolites from maternal paracrine in finetuning embryonic epigenomic reprogramming during early development.

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Section: Introductionsupporting

confidence: 64%

Vitamin C Rescues in vitro Embryonic Development by Correcting Impaired Active DNA Demethylation

Chu

Yao

et al. 2021

Front. Cell Dev. Biol.

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“…76 Inhibition of the FGF signaling pathway leads to DNMT3B inhibition and DNA methylation defects. 77 In our study, dnmt3bb2 was significantly downregulated, suggesting that DNA methylation may interact with the expression of her5 during FGF signaling. lf ng can regulate the synchronized oscillation of the segmentation clock by notch signaling.…”

Section: Combined Effects Of Bmdbm and Ps-npbs On Genesupporting

confidence: 50%

“…her5 also directs neuronal differentiation in a precise spatiotemporal manner in the midbrain, and the expression of her5 is controlled by Wnt regulation of FGF signaling . Inhibition of the FGF signaling pathway leads to DNMT3B inhibition and DNA methylation defects . In our study, dnmt3bb2 was significantly downregulated, suggesting that DNA methylation may interact with the expression of her5 during FGF signaling.…”

Section: Resultsmentioning

confidence: 46%

Effects of Nanoplastics and Butyl Methoxydibenzoylmethane on Early Zebrafish Embryos Identified by Single-Cell RNA Sequencing

Liu

Wang

Ling

et al. 2021

Environ. Sci. Technol.

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Nanoplastics with small particle sizes and high surface area/volume ratios easily absorb environmental pollutants and affect their bioavailability. In this study, polystyrene nanoplastic beads (PS-NPBs) with a particle size of 100 nm and butyl methoxydibenzoylmethane (BMDBM) sunscreen in personal-care products were chosen as target pollutants to study their developmental toxicity and interactive effects on zebrafish embryos. The exposure period was set from 2 to 12 h postfertilization (hpf). BMDBM and PS-NPBs significantly upregulated genes related to antioxidant enzymes and downregulated the gene expression of aromatase and DNA methyltransferases, but the influenced genes were not exactly the same. The combined exposure reduced the adverse effects on the expression of all genes. With the help of the single-cell RNA sequencing technology, neural mid cells were identified as the target cells of both pollutants, and brain development, head development, and the notch signaling pathway were the functions they commonly altered. The key genes and functions that are specifically affected by BMDBM and/or PS-NPBs were identified. BMDBM mainly affects the differentiation and fate of neurons in the central nervous system through the regulation of her5, her6, her11, lfng, pax2a, and fgfr4. The PS-NPBs regulate the expression of olig2, foxg1a, fzd8b, six3a, rx1, lhx2b, nkx2.1a, and sfrp5 to alter nervous system development, retinal development, and stem cell differentiation. The phenotypic responses of zebrafish larvae at 120 hpf were tested, and significant inhibition of locomotor activity was found, indicating that early effects on the central nervous system would have a sustained impact on the behavior of zebrafish.

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“…In mice, DNMT3B deficiency severely damages post-implantation development ( Okano et al, 1999 ). Also, inactivation of DNMT3B in biparental embryos induces global DNA hypomethylation ( Kato et al, 2007 ; Auclair et al, 2014 ; Fu et al, 2020 ). Although it remains unknown whether lower DNMT3B expression promotes global hypomethylation in bovine hAE.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated Gene Expression of Imprinted and X-Linked Genes: A Link to Poor Development of Bovine Haploid Androgenetic Embryos

Águila

Suzuki

Hill

et al. 2021

Front. Cell Dev. Biol.

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Mammalian uniparental embryos are efficient models for genome imprinting research and allow studies on the contribution of the paternal and maternal genomes to early embryonic development. In this study, we analyzed different methods for production of bovine haploid androgenetic embryos (hAE) to elucidate the causes behind their poor developmental potential. Results indicate that hAE can be efficiently generated by using intracytoplasmic sperm injection and oocyte enucleation at telophase II. Although androgenetic haploidy does not disturb early development up to around the 8-cell stage, androgenetic development is disturbed after the time of zygote genome activation and hAE that reach the morula stage are less capable to reach the blastocyst stage of development. Karyotypic comparisons to parthenogenetic- and ICSI-derived embryos excluded chromosomal segregation errors as causes of the developmental constraints of hAE. However, analysis of gene expression indicated abnormal levels of transcripts for key long non-coding RNAs involved in X chromosome inactivation and genomic imprinting of the KCNQ1 locus, suggesting an association with X chromosome and some imprinted loci. Moreover, transcript levels of methyltransferase 3B were significantly downregulated, suggesting potential anomalies in hAE establishing de novo methylation. Finally, the methylation status of imprinted control regions for XIST and KCNQ1OT1 genes remained hypomethylated in hAE at the morula and blastocyst stages, confirming their origin from spermatozoa. Thus, our results exclude micromanipulation and chromosomal abnormalities as major factors disturbing the normal development of bovine haploid androgenotes. In addition, although the cause of the arrest remains unclear, we have shown that the inefficient development of haploid androgenetic bovine embryos to develop to the blastocyst stage is associated with abnormal expression of key factors involved in X chromosome activity and genomic imprinting.

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Repression of FGF signaling is responsible for Dnmt3b inhibition and impaired de novo DNA methylation during early development of in vitro fertilized embryos

Cited by 10 publications

References 65 publications

Vitamin C Rescues in vitro Embryonic Development by Correcting Impaired Active DNA Demethylation

Vitamin C Rescues in vitro Embryonic Development by Correcting Impaired Active DNA Demethylation

Effects of Nanoplastics and Butyl Methoxydibenzoylmethane on Early Zebrafish Embryos Identified by Single-Cell RNA Sequencing

Dysregulated Gene Expression of Imprinted and X-Linked Genes: A Link to Poor Development of Bovine Haploid Androgenetic Embryos

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