Loss of H3K27me3 Imprinting in Somatic Cell Nuclear Transfer Embryos Disrupts Post-Implantation Development

Matoba, Shogo; Wang, Huihan; Jiang, Lan; Lu, Falong; Iwabuchi, Kumiko A.; Wu, Xiumei; Inoue, Kimiko; Yang, Lin; Press, William; Lee, Jeannie T.; Ogura, Atsuo; Shen, Li; Zhang, Yi

doi:10.1016/j.stem.2018.06.008

Cited by 111 publications

(121 citation statements)

References 62 publications

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“…In addition to our results on the MT2A deletion allele, the importance of the LIT-induced igDMR for allelic usage is also supported by the observation of imprinted expression at Slc38a4 in embryonic and adult epiblast-derived tissues in which the igDMR, but not the intragenic H3K27me3 domain, is present ( Supplementary Fig. 10 ) 33,49 . The paradoxical critical role of two different maternal epigenetic marks laid down in two different regions of the Slc38a4 locus may be reconciled by the fact that an alternative annotated TSS of the Slc38a4 gene is located downstream of the igDMR and is embedded within the intragenic region enriched for H3K27me3 described by Inoue and colleagues 47 .…”

Section: Discussionsupporting

confidence: 84%

“…To validate previously identified maternally methylated imprinted gDMRs (igDMRs) 21–24 , we interrogated DNAme profiles from published whole genome bisulfite sequencing data from gametes, placenta and somatic tissues ( Supplementary Table 1 ) 56 . Specifically, we identified regions that are hypermethylated (> 70% DNAme) in oocytes, hypomethylated (< 30% DNAme) in sperm, retain DNAme (>25%) in the blastocyst, and show 35-65% DNAme in placenta (purified first-trimester cytotrophoblast; CT) or at least one adult somatic tissue 4,5,7,8,18,19,29,40,41,44,47,49,57–69 . We further validated and refined this list by only including gDMRs harboring either reported maternal, monoallelic or bimodal DNAme in the placenta and/or at least one somatic tissue.…”

Section: Methodsmentioning

confidence: 99%

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Evolution of imprinting via lineage-specific insertion of retroviral promoters

Bogutz

Brind’Amour

Kobayashi

et al. 2019

Preprint

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26Imprinted genes are expressed from a single parental allele. In mammals, this unusual mode of 27 transcription generally depends on the epigenetic silencing of one allele by DNA methylation 28 (DNAme) established in the germline. While many species-specific imprinted orthologues have been 29 documented in eutherians, the molecular mechanisms underlying the evolutionary switch from biallelic 30 to imprinted expression are currently unknown. During mouse oogenesis, gametic differentially 31 methylated regions (gDMRs) acquire DNAme in a process guided by transcription. Here we show that 32 transcription initiating in proximal lineage-specific endogenous retroviruses (ERVs) is likely 33 responsible for DNAme established in oocytes at 4/6 mouse-specific and 17/110 human-specific 34 maternal imprinted gDMRs (igDMRs). The latter can be further divided into Catarrhini (Old World 35 monkeys and apes)-or Hominoidea (ape)-specific igDMRs, which are embedded within transcription 36 units initiating in ERVs specific to these primate lineages. Using CRISPR-Cas9 mutagenesis, we 37 deleted the relevant murine-specific ERVs upstream of the maternally methylated genes Impact and 38Slc38a4. Strikingly, imprinting at these genes was lost in the offspring of females harboring these 39 deletions and biallelic expression was observed. Our work reveals a novel evolutionary mechanism 40 whereby maternally silenced genes arise from biallelically expressed progenitors. 41 42 43 During postnatal oocyte growth in mammals, transcribed genomic regions acquire two characteristic 44 epigenetic marks: transcription-coupled trimethylation at lysine 36 of histone H3 (H3K36me3) 1 and 45 DNAme 2-5 . In both human and mouse female germline, the overall levels of CpG methylation increase 46 from less than 5% in post-migratory primordial germ cells (PGCs) to ~40-50% in fully-grown, 47 germinal vesicle oocytes (GVOs) 4,6-8 Kobayashi:2013ia}. In growing murine oocytes, 85-90% of this 48 DNAme is deposited over H3K36me3-marked transcribed regions of the genome 3 . Notably, we 49 recently demonstrated that SETD2-dependent deposition of H3K36me3 is required for de novo 50 3 DNAme of transcribed gene bodies in mouse oocytes 9 . Such transcription-coupled de novo DNAme is 51 also responsible for the establishment of regions of differential DNAme between the mature gametes 52 (gametic differentially methylated regions, gDMRs), a subset of which are maintained throughout 53 preimplantation development. This unique class of gDMRs, the imprinted gDMRs (igDMRs), can 54 direct imprinted paternal allele-specific expression of the gene(s) under their regulation, the imprinted 55 genes 3,10,11 . Importantly, transcription initiating within upstream oocyte-specific promoters has been 56 reported to play a critical role in de novo DNAme at the maternal igDMRs of a number of mouse 57 imprinted genes 3,12-16 , but the evolutionary origin of such promoters remains unexplored. 58 59 Specific families of ERVs, also known as long terminal repeat (LTR) retrotransposons, are 6...

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Section: Discussionsupporting

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Evolution of imprinting via lineage-specific insertion of retroviral promoters

Bogutz

Brind’Amour

Kobayashi

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Related studies have demonstrated that the ectopic expression of Xist in SCNT derived embryos could be corrected by siRNA-Xist, leading to more than a 10-fold increase in the birth rate of male clones [3, 49, 50]. To examine whether the combination of siRNA-Xist and siRNA-6B could further improve SCNT embryonic full-term development.…”

Section: Resultsmentioning

confidence: 99%

“…Bai et al claimed that H3K27me3 removal corrected SCNT-specific aberrant XCI status in cloned embryos. This was especially of interest since it was recently reported that H3K27me3 serves as the imprinting mark of Xist, and loss of H3K27me3 induces Xist ectopic expression [47, 50]. To further determine the role of KDM6A in the XCI of SCNT, we injected KDM6A mRNA (1,000 ng/μl) into SCNT embryos, and found that the developmental efficiency of SCNT embryos was reduced, while many X-linked genes were consistently repressed.…”

Section: Discussionmentioning

confidence: 99%

Fine Tuning of Histone Demethylase KDM6A/B Improves the Development of Nuclear Transfer Embryo

Yang

Song

Liu

et al. 2018

Preprint

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“…3e). Notably, H3K27me3 was recently implicated in transcriptional silencing of genes subject to non-canonical maternal imprinting in the mouse 41,57 . These results reveal that at the 2C stage, the paternal and maternal alleles of a subset of PDA loci are distinctly marked by DNAme and H3K27me3, respectively.…”

Section: Most Pda Target Genes Are Expressed During Spermatogenesis Amentioning

confidence: 99%

Maternal DNMT3A-dependent de novo methylation of the zygotic paternal genome inhibits gene expression in the early embryo

Albert

Yeung

Toriyama

et al. 2020

Preprint

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De novo DNA methylation (DNAme) during mammalian spermatogenesis yields a densely methylated genome, with the exception of CpG islands (CGIs), which are hypomethylated in sperm. Following fertilization, the paternal genome undergoes widespread DNAme loss before the first S-phase. Paradoxically, recent mass spectrometry analysis revealed that a low level of de novo DNAme occurs exclusively on the zygotic paternal genome. However, the loci involved and impact on genic transcription was not addressed. Here, we employ allele-specific analysis of wholegenome bisulphite sequencing (WGBS) data and show that a number of genomic regions, including several dozen CGI promoters, are de novo methylated on the paternal genome in 2-cell embryos. A subset of these promoters maintains DNAme through development to the blastocyst stage. Consistent with zygotic paternal DNAme acquisition (PDA), many of these loci are hypermethylated in androgenetic blastocysts but hypomethylated in parthenogenetic blastocysts. Strikingly, PDA is lost following maternal deletion of Dnmt3a. Furthermore, a subset of promoters showing PDA which are normally transcribed from the paternal allele in blastocysts show premature transcription at the 4-cell stage in maternal Dnmt3a knockout embryos. These observations uncover an unexpected role for maternal DNMT3A activity in postfertilization epigenetic reprogramming and transcriptional silencing of the paternal genome.

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Loss of H3K27me3 Imprinting in Somatic Cell Nuclear Transfer Embryos Disrupts Post-Implantation Development

Cited by 111 publications

References 62 publications

Evolution of imprinting via lineage-specific insertion of retroviral promoters

Evolution of imprinting via lineage-specific insertion of retroviral promoters

Fine Tuning of Histone Demethylase KDM6A/B Improves the Development of Nuclear Transfer Embryo

Maternal DNMT3A-dependent de novo methylation of the zygotic paternal genome inhibits gene expression in the early embryo

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