Dynamic Heterogeneity of Brachyury in Mouse Epiblast Stem Cells Mediates Distinct Response to Extrinsic Bone Morphogenetic Protein (BMP) Signaling

Song, Lu; Peng, Guangdun; Tang, Ke; Jing, Naihe

doi:10.1074/jbc.m115.705418

Cited by 15 publications

(13 citation statements)

References 73 publications

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“…We found that T expression was confined almost exclusively to cluster D4_G2 (272/1154 or 24%). T was also sporadically expressed in the primed pluripotent cluster D4_G1 (25/1351 or 2%), consistent with previous reports of T expression in EpiSC (Song et al, 2016), and it was also rarely detected in cluster D4_G3 (6/1794 or < 1%). To better understand the biological pathways active in the T -expressing cluster D4_G2, we examined the gene set enrichment results.…”

Section: Resultssupporting

confidence: 90%

“…Clusters D4_G5 and D4_G6 were characterized by high levels of pluripotency genes such as Zfp42, Dppa3, Tcf15, and Cbx7, the ESC-specific Polycomb repressive complex 1 ( PRC1 ) member (O'Loghlen et al, 2012). Cluster D4_G1 contains genes characteristic of post-implantation epiblast cells and EpiSCs such as Fgf5 (Khoa et al, 2016), Dnmt3b (Watanabe et al, 2002), and Pou3f1 (Song et al, 2016). Cluster D4_G2 contains genes indicative of the primitive streak stage gastrula including T and Fgf8 (Mikawa et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

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A single cell transcriptional portrait of embryoid body differentiation and comparison to progenitors of the developing embryo

Spangler

Craft

et al. 2018

Stem Cell Research

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Directed differentiation of pluripotent stem cells provides an accessible system to model development. However, the distinct cell types that emerge, their dynamics, and their relationship to progenitors in the early embryo has been difficult to decipher because of the cellular heterogeneity inherent to differentiation. Here, we used a combination of bulk RNA-Seq, single cell RNA-Seq, and bioinformatics analyses to dissect the cell types that emerge during directed differentiation of mouse embryonic stem cells as embryoid bodies and we compared them to spatially and temporally resolved transcriptional profiles of early embryos. Our single cell analyses of the day 4 embryoid bodies revealed three populations which had retained related yet distinct pluripotent signatures that resemble the pre- or post-implantation epiblast, one population of presumptive neuroectoderm, one population of mesendoderm, and four populations of neural progenitors. By day 6, the neural progenitors predominated the embryoid bodies, but both a small population of pluripotent-like cells and an anterior mesoderm-like Brachyury-expressing population were present. By comparing the day 4 and day 6 populations, we identified candidate differentiation paths, transcription factors, and signaling pathways that mark the in vitro correlate of the transition from the mid-to-late primitive streak stage.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

A single cell transcriptional portrait of embryoid body differentiation and comparison to progenitors of the developing embryo

Spangler

Craft

et al. 2018

Stem Cell Research

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“…Findings from studies of mouse primed cells support this possibility because different mEpiSC lines exhibit distinct gene expression patterns, and some mEpiSC lines exhibit resistance to differentiation into neural lineages ( Bernemann et al., 2011 ). Consistent with these findings, Song et al. (2016) report that, even in the cell line, mEpiSCs exhibit heterogeneity and biased differentiation potential.…”

Section: Discussionsupporting

confidence: 72%

Naive-like ESRRB+ iPSCs with the Capacity for Rapid Neural Differentiation

et al. 2017

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SummarySeveral groups have reported the existence of a form of pluripotency that resembles that of mouse embryonic stem cells (mESCs), i.e., a naive state, in human pluripotent stem cells; however, the characteristics vary between reports. The nuclear receptor ESRRB is expressed in mESCs and plays a significant role in their self-renewal, but its expression has not been observed in most naive-like human induced pluripotent stem cells (hiPSCs). In this study, we modified several methods for converting hiPSCs into a naive state through the transgenic expression of several reprogramming factors. The resulting cells express the components of the core transcriptional network of mESCs, including ESRRB, at high levels, which suggests the existence of naive-state hiPSCs that are similar to mESCs. We also demonstrate that these cells differentiate more readily into neural cells than do conventional hiPSCs. These features may be beneficial for their use in disease modeling and regenerative medicine.

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“…Mammalian somatic cells originate from the epiblast in postimplantation embryos. The success in establishing epiblast stem cells (EpiSCs) from the epiblasts of egg-cylinder-stage mouse embryos ( Brons et al, 2007 ; Tesar et al, 2007 ; Sumi et al, 2013 ) created new opportunities for investigating the gene regulatory networks in the epiblast and for deriving specific somatic cell lineages ( Iwafuchi-Doi et al, 2011 , 2012 ; Acampora et al, 2013 ; Factor et al, 2014 ; Kojima et al, 2014 ; Matsuda and Kondoh, 2014 ; Tsakiridis et al, 2014 ; Henrique et al, 2015 ; Li et al, 2015 ; Song et al, 2016 ). EpiSCs can be maintained in feeder-free culture conditions supplemented with activin, which is a Nodal replacement, and bFGF (FGF2) ( Brons et al, 2007 ; Iwafuchi-Doi et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

ChIP-seq analysis of genomic binding regions of five major transcription factors in mouse epiblast stem cells that highlights a central role for ZIC2

et al. 2017

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To obtain insight into the transcription factor (TF)-dependent regulation of epiblast stem cells (EpiSCs), we performed ChIP-seq analysis of the genomic binding regions of five major TFs. Analysis of in vivo biotinylated ZIC2, OTX2, SOX2, POU5F1 and POU3F1 binding in EpiSCs identified several new features. (1) Megabase-scale genomic domains rich in ZIC2 peaks and genes alternate with those rich in POU3F1 but sparse in genes, reflecting the clustering of regulatory regions that act at short and long-range, which involve binding of ZIC2 and POU3F1, respectively. (2) The enhancers bound by ZIC2 and OTX2 prominently regulate TF genes in EpiSCs. (3) The binding sites for SOX2 and POU5F1 in mouse embryonic stem cells (ESCs) and EpiSCs are divergent, reflecting the shift in the major acting TFs from SOX2/POU5F1 in ESCs to OTX2/ZIC2 in EpiSCs. (4) This shift in the major acting TFs appears to be primed by binding of ZIC2 in ESCs at relevant genomic positions that later function as enhancers following the disengagement of SOX2/POU5F1 from major regulatory functions and subsequent binding by OTX2. These new insights into EpiSC gene regulatory networks gained from this study are highly relevant to early stage embryogenesis.

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Dynamic Heterogeneity of Brachyury in Mouse Epiblast Stem Cells Mediates Distinct Response to Extrinsic Bone Morphogenetic Protein (BMP) Signaling

Cited by 15 publications

References 73 publications

A single cell transcriptional portrait of embryoid body differentiation and comparison to progenitors of the developing embryo

A single cell transcriptional portrait of embryoid body differentiation and comparison to progenitors of the developing embryo

Naive-like ESRRB+ iPSCs with the Capacity for Rapid Neural Differentiation

ChIP-seq analysis of genomic binding regions of five major transcription factors in mouse epiblast stem cells that highlights a central role for ZIC2

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