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Landscape of TFs binding in mouse early embryos [Bisulfite-seq]

ABSTRACT: In mammals, early lineage specification originates from the establishment of cell polarization in early embryos, before providing the foundation for all somatic development. Although there have been heated debates about whether transcription factors (TFs) or epigenetic information plays the dominant role in cell fate decisions, the precise annotation of TFs remains largely elusive in early embryos, restricting the functional study of developmentally important TFs. Here, we investigated the genome-wide landscapes of two known triggers of mouse embryo polarization: transcription factor AP-2 gamma (Tfap2c) and TEA domain transcription factor 4 (Tead4). We found that Tfap2c can bridge the connection between the promoter and the proximal enhancer, and further facilitate the functions of downstream Tead4 and Klf5 in boosting polarization. Our study also implicated that Rarg-initiated active demethylation might be a prerequisite for proper Tfap2c functioning. Furthermore, the results demonstrated that both genomic imprinting and nucleotide polymorphism can instruct TF binding, leading to allele-specific expression in early embryos. Overall, our study characterized TF dynamics during the peri-implantation stage and revealed their spatiotemporal interactions with the epigenetic environment in driving polarization and lineage specification.

ORGANISM(S): Mus musculus

PROVIDER: GSE248696 | GEO | 2024/03/03

REPOSITORIES: GEO

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Project description:The germ cell lineage ensures the continuity of life through the generation of male and female gametes, which unite to form a totipotent zygote. We have established a culture system that recapitulates the mouse germ-cell specification pathway: Using cytokines, embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) are induced into epiblast-like cells (EpiLCs) and then into primordial germ cell-like cells (PGCLCs) with capacity both for spermatogenesis and oogenesis, creating an opportunity for understanding and regulating mammalian germ cell development in both sexes in vitro. Here we show that, without cytokines, simultaneous over-expression of three transcription factors (TFs), Blimp1 (also known as Prdm1), Prdm14 and Tfap2c (also known as AP2γ), directs EpiLCs, but not ESCs, swiftly and highly efficiently into a PGC state with endogenous transcription circuitry. The induction of the PGC state on EpiLCs minimally requires Prdm14 but not Blimp1 or Tfap2c. The TF-induced PGC state reconstitutes key transcriptome and epigenetic reprogramming in PGCs, but bypasses a mesodermal program that accompanies PGC specification in vivo and in vitro by cytokines including BMP4. Importantly, the TF-induced PGC-like cells robustly contribute to spermatogenesis and fertile offspring. Our findings provide not only a novel insight into the transcriptional logic that creates a germ cell state, but also a foundation for the TF-based reconstitution and regulation of mammalian gametogenesis. Aim of this analysis is characterization of transcription factor-induced primordial germ cells (TF-PGCLCs) compared with cytokine-induced primordial germ cells (Ck-PGCLCs) (Hayashi et al., 2011, Cell), epiblast-like cells (EpiLCs) (Hayashi et al., 2011, Cell), and embryonic stem cells (ESCs) and identification of genes differentially expressed among them. TF-PGCLCs induced by multiple combinations of TFs (Blimp1 (B), Prdm14 (P14), and Tfap2c (A) (BP14A), BP14, P14A, P14) on day 2 and 4 (for BP14A cells) of the induction were also compared. Parental clone without exogenous TFs cultured with doxycycline, are also included as a negative control. Ck-PGCLCs day 2 and day 4 samples, which are previously unreported, EpiLCs and ESCs used in this study were also included. Overexpression of exogenous three TFs in ESCs yields stella-ECFP (SC) positive cells, which were sorted and included in the analysis. cDNA samples, prepared from approximately 20,000 cells, were amplified with a quantitative global PCR method (Kurimoto et al., 2006, Nucleic Acids Research). Two biological duplicates for each cell type were analyzed. Samples from GSE30056 were also included and reanalysed (GSM1070855-GSM1070864).

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Landscape of TFs binding in mouse early embryos [Bisulfite-seq]

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