An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feed Forward Loop Interactions

Sevilla, Ana; Papatsenko, Dimitri; Mazloom, Amin R.; Xu, Huilei; Vasil’eva, A. A.; Unwin, Richard D.; LeRoy, Gary; Chen, Edward Y.; Garrett-Bakelman, Francine E.; Lee, Dung‐Fang; Trinité, Benjamín; Webb, Ryan L; Wang, Zichen; Su, Jie; Gingold, Julian A.; Melnick, Ari; Garcia, Benjamin A.; Whetton, Anthony D.; MacArthur, Ben D.; Ma’ayan, Avi; Lemischka, Ihor R.

doi:10.3389/fcell.2021.630067

Cited by 11 publications

(20 citation statements)

References 45 publications

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“…However, ESRRB overexpression in Nanog -/-ESCs does not fully recapitulate the effect of NANOG overexpression on ESC self-renewal (Festuccia et al, 2012). Although NANOG and ESRRB share common target genes (Festuccia et al, 2012), functional differences between NANOG and ESRRB exist since distinct subsets of genes are specifically regulated by either TF in ESCs (Sevilla et al, 2021).…”

Section: Discussionmentioning

confidence: 94%

Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry

Vojtek

Zhang

Sun

et al. 2021

Preprint

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Primordial germ cells (PGCs) are induced in the embryo by signals, including BMP emanating from extra-embryonic ectoderm, that act on cells in the post-implantation epiblast. PGC development can be recapitulated in vitro through the exposure of epiblast-like cells (EpiLCs) to appropriate cytokines, resulting in differentiation into PGC-like cells (PGCLCs). Interestingly, the requirement for cytokines to induce PGCLCs can be bypassed by enforced expression of the transcription factor (TF) NANOG. However, the underlying mechanisms are not fully elucidated. Here, we show that Otx2 downregulation is essential to enable NANOG to induce PGCLC formation. Moreover, while previous work has shown that the direct NANOG target gene Esrrb can substitute for several functions of NANOG, enforced expression of ESRRB cannot promote PGCLC specification from EpiLCs. This appears to be due to differential downregulation of Otx2 by NANOG and ESRRB, since induction of ESRRB in Otx2+/- EpiLCs activates expression of the core PGC TFs, Blimp1, Prdm14 and Ap2γ and emergence of PGCLCs. This study illuminates the interplay of TFs occurring at the earliest stages of PGC specification from a state of competence.

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Section: Discussionmentioning

confidence: 94%

Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry

Vojtek

Zhang

Sun

et al. 2021

Preprint

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“…CeSpGRN-TF detected top-ranking edges including Pou5f1 - Nanog, Esrrb - Nanog, Sox2 - Otx2 , and Sox2 - Tcf7 . Those edges were discussed to be the key regulatory interactions for mESC differentiation in literature [42, 43, 44]. This can suggest that key regulatory interactions need not be active throughout the differentiation process but their strengths can be low at certain stages.…”

Section: Resultsmentioning

confidence: 99%

CeSpGRN: Inferring cell-specific gene regulatory networks from single cell multi-omics and spatial data

Zhang

Jongseok

Song

et al. 2022

Preprint

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Single cell gene expression datasets have been used to uncover differences between single cells, leading to discoveries of new cell types and cell identities, which are usually defined by the transcriptome profiles of cells. Biological networks, in particular, gene regulatory networks (GRNs), can be viewed as another feature of the cells, that contributes to the uniqueness of each single cell. However, methods that reconstruct cell-specific GRNs are still missing. We propose CeSpGRN (Cell Specific GRN), which infers cell-specific GRNs from single cell gene expression data. CeSpGRN uses a Gaussian weighted kernel which allows the GRN of a given cell to be learned from the gene expression profile of this cell and cells that are upstream and downstream of this cell in the developmental process. CeSpGRN can be applied to infer cell-specific GRNs in cell populations of any trajectory or cluster structure, and it does not require time information of cells as additional input. We compared the performance of CeSpGRN and baseline methods on simulated datasets obtained under various settings. CeSpGRN showed superior performance in reconstructing the GRN for each cell, as well as in detecting the regulatory interactions that differ between cells. We also applied CeSpGRN to real datasets including THP-1 human myeloid monocytic leukemia cells and mouse embryonic stem cells, where CeSpGRN suggested a set of interactions between genes that rewire during the differentiation process in these cells.

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“…However, ESRRB overexpression in Nanog −/− ESCs does not fully recapitulate the effect of NANOG overexpression on ESC self-renewal ( Festuccia et al., 2012 ). Although NANOG and ESRRB share common target genes ( Festuccia et al., 2012 ), distinct subsets of genes are regulated by either TF in ESCs ( Sevilla et al., 2021 ). In addition, although the interactomes of NANOG and ESRRB contain common binding partners ( Gagliardi et al., 2013 ; van den Berg et al., 2010 ), ESRRB, but not NANOG, interacts with Mediator, suggesting that ESRRB may function prominently in transcriptional initiation.…”

Section: Discussionmentioning

confidence: 99%

Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry

et al. 2022

View full text Add to dashboard Cite

Primordial germ cells (PGCs) arise from cells of the post-implantation epiblast in response to cytokine signaling. PGC development can be recapitulated in vitro by differentiating epiblast-like cells (EpiLCs) into PGC-like cells (PGCLCs) through cytokine exposure. Interestingly, the cytokine requirement for PGCLC induction can be bypassed by enforced expression of the transcription factor (TF) NANOG. However, the underlying mechanisms are not fully elucidated. Here, we show that NANOG mediates Otx2 downregulation in the absence of cytokines and that this is essential for PGCLC induction by NANOG. Moreover, the direct NANOG target gene Esrrb, which can substitute for several NANOG functions, does not downregulate Otx2 when overexpressed in EpiLCs and cannot promote PGCLC specification. However, expression of ESRRB in Otx2 +/À EpiLCs rescues emergence of PGCLCs. This study illuminates the interplay of TFs occurring at the earliest stages of PGC specification.

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An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feed Forward Loop Interactions

Cited by 11 publications

References 45 publications

Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry

Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry

CeSpGRN: Inferring cell-specific gene regulatory networks from single cell multi-omics and spatial data

Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry

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