Single-cell DNA methylome sequencing of human preimplantation embryos

Zhu, Ping; Guo, Hongshan; Ren, Yixuan; Hou, Yu; Dong, Ji; Li, Rong; Lian, Ying; Fan, Xiaoying; Hu, Boqiang; Gao, Yun; Wang, Xiaoye; Yuan, Wei; Liu, Ping; Yan, Jie; Ren, Xiaojun; Yuan, Peng; Yuan, Yifeng; Yan, Zhiqiang; Wen, Lu; Yan, Liying; Qiao, Jie; Tang, Fuchou

doi:10.1038/s41588-017-0007-6

Cited by 244 publications

(246 citation statements)

References 37 publications

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“…A recent study of 49 disaggregated cleavage-stage rhesus macaque embryos used scDNA-seq to demonstrate that 13 were euploid, 9 were affected by solely meiotic errors, and the remaining 27 by mitotic errors or errors of ambiguous origin (Daughtry et al 2019) . Our estimates are also roughly consistent with aneuploidy calls based on scDNA-and scRNA-seq of human blastocysts (Zhu et al 2018;Zhou et al 2019) , which reported evidence of mitotic-origin aneuploidy in more than half of embryos.…”

Section: Discussionsupporting

confidence: 88%

“…Nevertheless, our study places bounds on any potential differences and provides a useful quantitative framework for testing such hypotheses in future single-cell datasets. While we replicated this lack of enrichment using scDNA-seq-based calls from additional preimplantation embryos (Zhu et al 2018) , we detected significant enrichment of aneuploidy in the trophectoderm versus the primitive endoderm and epiblast (lineages derived from the inner cell mass) in published data from postimplantation embryos (Zhou et al 2019) . Notably, the latter dataset included nearly 6000 cells, lending greater statistical power to such comparisons.…”

Section: Discussionsupporting

confidence: 58%

“…Though informative of cell type, the sparse and bursty nature of scRNA-seq data poses a challenge for aneuploidy inference, placing practical limits on sensitivity and specificity (Griffiths et al 2017) . We thus sought to replicate the qualitative patterns of mosaic aneuploidy that we previously described using published data from additional disaggregated embryos that were analyzed by single-cell post-bisulfite adaptor tagging (PBAT) DNA methylome sequencing (Zhu et al 2018) . The fact that these data were based on single-cell DNA-sequencing (scDNA-seq) lends confidence to the aneuploidy calls.…”

Section: Cell-type Specific Variation In Aneuploidy May Arise and Intmentioning

confidence: 99%

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Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Starostik

Sosina

McCoy

2020

Preprint

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Less than half of human zygotes survive to live birth, primarily due to aneuploidies of meiotic or mitotic origin. Mitotic errors lead to chromosomal mosaicism, defined by multiple cell lineages with distinct chromosome complements. The incidence and fitness consequences of chromosomal mosaicism in human embryos remain controversial, with most previous studies based on bulk DNA assays or comparisons of multiple biopsies of a few embryonic cells. Single-cell genomic data provide an opportunity to quantify mosaicism on an embryo-wide scale. To this end, we extended an approach to infer aneuploidies based on chromosome dosage-associated changes in gene expression by integrating signatures of allelic imbalance. We applied this method to published single-cell RNA sequencing data from 74 disaggregated human embryos, spanning the morula to blastocyst stages. Our analysis revealed widespread mosaic aneuploidies across preimplantation development, with 59 of 74 (80%) embryos harboring at least one aneuploid cell (1% FDR). By clustering copy number calls, we reconstructed histories of chromosome mis-segregation, distinguishing meiotic and early mitotic errors from those occurring after lineage differentiation. We observed no significant enrichment of aneuploid cells in the trophectoderm compared to the inner cell mass, though we do detect such an enrichment in published data from later post-implantation stages. Finally, we observed that aneuploid cells exhibit upregulation of immune response genes, as well as downregulation of genes involved in proliferation, metabolism, and protein processing, consistent with stress responses previously documented in other stages and systems. Together, our work provides a high-resolution view of aneuploidy in preimplantation embryos and supports the conclusion that low-level mosaicism is a common feature of early human development.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 58%

Section: Cell-type Specific Variation In Aneuploidy May Arise and Intmentioning

confidence: 99%

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Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Starostik

Sosina

McCoy

2020

Preprint

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“…1d, e, 2, and 3) EWAS control was used. The developmental epigenetic gene sets were represented by demethylation resistant genes observed in blastocyst, epiblast, and primordial germ cells in mice 3,29 , genes that retain sperm methylation pattern in inner cell mass and trophectoderm cells isolated from human blastocysts, and demethylation resistance genes observed in primordial germ cells in humans 4,30 . Notably, the sperm gene set, not the control, showed overrepresentation of developmental epigenetic genes in general, in both mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Multi-omics data analysis implicating epigenetic inheritance in evolution and disease

Sharma

2019

Preprint

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Recent evidence surprisingly suggests existence of germline mediated epigenetic inheritance in diverse species including mammals. The evolutionary and health implications as well as the mechanistic plausibility of epigenetic inheritance are subjects of immense current interest and controversy, with integrative analysis expected to provide valuable insights. Here, an unbiased gene set enrichment analysis of existing multi-omics data is presented that readily supports a role of sperm DNA methylome in evolution and disease, as also in developmental mechanisms. In mice, differentially methylated sperm genes in cold induced inheritance specifically overrepresent genes associated with cold adaptation. Similarly, in humans, differentially methylated sperm genes associate with disease and adaptation in general, with specific disease association supported by prior evidence. Further, the sperm genes, like disease and adaptation genes, overrepresent genes known to exhibit higher mutability, loss-of-function intolerance, and haploinsufficiency. Finally, both mouse and human sperm genes show enrichment for genes that retain sperm methylation during development and are developmentally expressed. Together, the present analysis provides one-stop evidence to suggest that sperm DNA methylome acts as a melting pot of gene-environment interaction, inheritance, evolution, and health and disease.

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“…Regardless, whole-genome bisulphite sequencing (WGBS) analyses reveal that DNAme levels on both parental genomes reach a low point in inner cell mass (ICM) cells of embryonic day 3.5 (E3.5) mouse blastocysts, followed by widespread de novo DNAme during post-implantation development [16][17][18] . This wave of genome-wide demethylation followed by remethylation is conserved in human embryonic development, albeit with slower kinetics [19][20][21] . Notably, disruption of the machinery required for the establishment or maintenance of DNAme result in infertility and/or embryonic lethality in mice, revealing the importance of DNAme homeostasis in early mammalian development 7,8,13,[22][23][24][25][26][27] .…”

Section: Introductionmentioning

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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Single-cell DNA methylome sequencing of human preimplantation embryos

Cited by 244 publications

References 37 publications

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Multi-omics data analysis implicating epigenetic inheritance in evolution and disease

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

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