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Zfp281 functions as a barrier in embryonic stem cells to extraembryonic endoderm stem cells differentiation [ChIP-seq]

ABSTRACT: Cell-fate decisions and lineage commitment in early embryonic development are governed by comprehensive gene-regulatory programs. However, the molecular details leading to initial segregation of different lineages remain unclear. In the second cell-fate decision, epiblast (EPI) and primitive endoderm (PrE) lineages are formed from the pluripotent inner cell mass (ICM) cells at blastocyst stage. Here, we demonstrated that the pluripotency transcription factor Zfp281 is a barrier in embryonic stem cells (ESCs) to PrE lineage differentiation. Zfp281 is expressed in extraembryonic endoderm cells (XENs), the ex vivo derivatives of PrE. But knockdown of Zfp281 doesn’t affect either maintenance or expression of the PrE master regulators in XENs. Using an in vitro differentiation protocol, we revealed that knockout of Zfp281 significantly increased the efficiency of ESC to XEN derivation. Using a Zfp281 rescue line for the knockout cells, we further confirmed that effects of elevated efficiency of XEN derivation is specifically due to loss of Zfp281. Mechanistically, we revealed that Zfp281 interacts with components in the polycomb repressive complex 2 (PRC2), and recruits PRC2 to promoters of PrE master regulators GATA4 and GATA6 for transcriptional and epigenetic repression. Taken together, our results demonstrated a novel role of Zfp281 in second cell-fate decision in embryonic stem cell differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE148231 | GEO | 2020/08/19

REPOSITORIES: GEO

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Zfp281 functions as a barrier in embryonic stem cells to extraembryonic endoderm stem cells differentiation [RNA-seq]

Project description:Cell-fate decisions and lineage commitment in early embryonic development are governed by comprehensive gene-regulatory programs. However, the molecular details leading to initial segregation of different lineages remain unclear. In the second cell-fate decision, epiblast (EPI) and primitive endoderm (PrE) lineages are formed from the pluripotent inner cell mass (ICM) cells at blastocyst stage. Here, we demonstrated that the pluripotency transcription factor Zfp281 is a barrier in embryonic stem cells (ESCs) to PrE lineage differentiation. Zfp281 is expressed in extraembryonic endoderm cells (XENs), the ex vivo derivatives of PrE. But knockdown of Zfp281 doesn’t affect either maintenance or expression of the PrE master regulators in XENs. Using an in vitro differentiation protocol, we revealed that knockout of Zfp281 significantly increased the efficiency of ESC to XEN derivation. Using a Zfp281 rescue line for the knockout cells, we further confirmed that effects of elevated efficiency of XEN derivation is specifically due to loss of Zfp281. Mechanistically, we revealed that Zfp281 interacts with components in the polycomb repressive complex 2 (PRC2), and recruits PRC2 to promoters of PrE master regulators GATA4 and GATA6 for transcriptional and epigenetic repression. Taken together, our results demonstrated a novel role of Zfp281 in second cell-fate decision in embryonic stem cell differentiation.

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Temporal RNA-seq expression profiling of Sox17-medaited XEN conversion of ESCs

Project description:The transcription factor Sox17 is expressed in early primitive endoderm-fated cells of the mouse embryo and in embryo-derived extraembryonic endoderm (ExEn) stem (XEN) cells. We have shown that overexpression of Sox17 in mouse embryonic stem cells (ESCs) drives cell fate to a committed XEN-like cell state (Sox17-XEN cells). When placed back into the embryo, Sox17-XEN cells contribute exclusively to the ExEn. Transient Sox17 expression is sufficient to drive this fate change during which time cells transit through distinct intermediate states prior to the generation of functional XEN-like cells. We identified dynamic regulatory networks driving Sox17-mediated XEN conversion by analyzing a dynamic regulatory map of gene expression bifurcation points throughout conversion, created using RNA-seq time series data. We found that Sox17 orchestrates this conversion process by acting in autoregulatory and feed-forward network motifs, regulating dynamic gene regulatory networks (GRNs) directing cell fate. We have shown that Sox17-mediated XEN conversion provides a powerful tool for understanding the regulation of cell fate changes and for the elucidation of GRNs regulating lineage decisions in the mouse embryo. Total RNA was extracted during a time course of Sox17 overexpression in mouse ESCs at 7 time points as well as from wild-type ESCs and wild-type XEN cells.

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