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Single-cell analysis of bidirectional reprogramming between early embryonic states reveals mechanisms of differential lineage plasticities [scATAC-seq]

ABSTRACT: Two distinct lineages, pluripotent epiblast (EPI) and primitive (extra-embryonic) endoderm (PrE), arise from common inner cell mass (ICM) progenitor cells in mammalian embryos. To study how these sister identities are forged, we leveraged embryonic (ES) and eXtraembryonic ENdoderm (XEN) stem cells – in vitro counterparts of the EPI and PrE. Bidirectional reprogramming between ES and XEN coupled with single-cell RNA and ATAC-seq analyses uncovered distinct rates, efficiencies and trajectories of state conversions, identifying drivers and roadblocks of reciprocal conversions. While GATA4-mediated ES-to-iXEN conversion was rapid and nearly deterministic, OCT4, KLF4 and SOX2-induced XEN-to-iPS reprogramming progressed with diminished efficiency and kinetics. A dominant PrE transcriptional program, safeguarded by Gata4, and globally elevated chromatin accessibility of EPI underscored the differential plasticities of the two states. Mapping in vitro to embryo trajectories revealed reprogramming in either direction tracked along, and toggled between, EPI and PrE in vivo states without transitioning through the ICM.

ORGANISM(S): Mus musculus

PROVIDER: GSE276702 | GEO | 2024/09/09

REPOSITORIES: GEO

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Single-cell analysis of bidirectional reprogramming between early embryonic states reveals mechanisms of differential lineage plasticities [scRNA-Seq]

Project description:Two distinct lineages, pluripotent epiblast (EPI) and primitive (extra-embryonic) endoderm (PrE), arise from common inner cell mass (ICM) progenitor cells in mammalian embryos. To study how these sister identities are forged, we leveraged embryonic (ES) and eXtraembryonic ENdoderm (XEN) stem cells – in vitro counterparts of the EPI and PrE. Bidirectional reprogramming between ES and XEN coupled with single-cell RNA and ATAC-seq analyses uncovered distinct rates, efficiencies and trajectories of state conversions, identifying drivers and roadblocks of reciprocal conversions. While GATA4-mediated ES-to-iXEN conversion was rapid and nearly deterministic, OCT4, KLF4 and SOX2-induced XEN-to-iPS reprogramming progressed with diminished efficiency and kinetics. A dominant PrE transcriptional program, safeguarded by Gata4, and globally elevated chromatin accessibility of EPI underscored the differential plasticities of the two states. Mapping in vitro to embryo trajectories revealed reprogramming in either direction tracked along, and toggled between, EPI and PrE in vivo states without transitioning through the ICM.

2024-09-09 | GSE276704 | GEO

Single-cell analysis of bidirectional reprogramming between early embryonic states reveals mechanisms of differential lineage plasticities [ATAC-Seq]

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Single-cell analysis of bidirectional reprogramming between early embryonic states reveals mechanisms of differential lineage plasticities [RNA-Seq]

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Project description:A blastocyst consists of three distinctive cell types: epiblast (EPI), trophoblast (TB), and primitive endoderm (PrE). Stem cell lines representing EPI and TB (embryonic stem (ES) cells and trophoblast stem (TS) cells) have been derived and they contribute to epiblast derivatives and trophoblast derivatives of stem cell-blastocyst chimeras, respectively. Although derived from PrE, extraembryonic endoderm (XEN) cells contribute to only a limited part of parietal endoderm (PE) but rarely to other PrE derivatives. Here we describe the establishment of primitive endoderm stem (PrES) cell lines in mice. PrES cells were derived and maintained in a serum-free media containing CHIR99021, FGF4, heparin, and PDGF-AA. RNA-seq analysis revealed that the transcriptome of PrES cells is globaly different from XEN cells: PrES cells express not only endoderm markers (Dab2, Gata4, Gata6, Sox17, etc.), but also pluripotent markers (Pou5f1, Cdh1, Nanog, Zfp42, etc.), and resembles in vivo founder PrE. PrES cells were rapidly and efficiently incorporated into PrE after blastocyst injection and efficiently contributed to all PrE derivatives, including PE, VE (visceral endoderm), and MZE (marginal zone endoderm) in chimeras. Importantly, PrES cells rescued embryonic lethality of PrE-depleted blastocysts by complementing all PrE derivatives. PrES cells thus not only contribute to understanding of the mechanisms of PrE specification but also provide a critical resource for artificial embryo reconstitution by stem cells alone.

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Mouse Global gene expression profiles of mouse embryonic day3.75 inner cell mass cells

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