Antagonistic Activities of Sox2 and Brachyury Control the Fate Choice of Neuro-Mesodermal Progenitors

Koch, Frank‐Thomas; Scholze, Manuela; Wittler, Lars; Schifferl, Dennis; Sudheer, Smita; Grote, Phillip; Timmermann, Bernd; Macura, Karol; Herrmann, Bernhard G.

doi:10.1016/j.devcel.2017.07.021

Cited by 151 publications

(223 citation statements)

References 63 publications

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“…Quantitative polymerase chain reaction (qPCR) revealed that the isolated T-positive hESCs expressed high levels of the mesoderm markers T(brachyury) and goosecoid (GSC), and the EMT marker Snai2, as compared to T-negative hESCs ( Figure 2E). Additionally, we found that direct transcriptional targets of T (Koch et al, 2017) were upregulated in the T-positive hESCs, verifying that the T-mNeonGreen fusion protein did not compromise downstream transcriptional activity of T ( Figure S2). By contrast, T-negative hESCs expressed high levels of the pluripotent marker Sox2, which also signifies ectodermal fate following gastrulation ( Figure 2E; Koch et al, 2017;Warmflash et al, 2014).…”

Section: Real-time Monitoring Of Hesc "Gastrulation-like" Nodessupporting

confidence: 67%

Mechanics regulate human embryonic stem cell self-organization to specify mesoderm

Muncie

Ayad

Lakins

et al. 2020

Preprint

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Embryogenesis is directed by morphogens that induce differentiation within a defined tissue geometry. Tissue organization is mediated by cell-cell and cell-extracellular matrix (ECM) adhesions and is modulated by cell tension and tissue-level force. Whether cell tension regulates development by directly influencing morphogen signaling remains unclear. Human embryonic stem cells (hESCs) exhibit an intrinsic capacity for self-organization that motivates their use as a tractable model of early human embryogenesis. We engineered patterned substrates that enhance cell-cell interactions to direct the self-organization of cultured hESCs into "gastrulation-like" nodes. Tissue geometries that generate local nodes of high cell-cell tension and induce these selforganized tissue nodes drive BMP4-dependent gastrulation by enhancing phosphorylation and nuclear translocation of β-catenin to promote Wnt signaling and mesoderm specification. The findings underscore the interplay between tissue organization, cell tension, and morphogendependent differentiation, and demonstrate that cell-and tissue-level forces directly regulate cell fate specification in early human development.

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Section: Real-time Monitoring Of Hesc "Gastrulation-like" Nodessupporting

confidence: 67%

Mechanics regulate human embryonic stem cell self-organization to specify mesoderm

Muncie

Ayad

Lakins

et al. 2020

Preprint

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“…S1B). NMPs are bipotential progenitor cells in the caudal region co-expressing Sox2 and T/Bra that undergo balanced differentiation to either spinal cord neuroectoderm or presomitic mesoderm to generate the post-cranial body axis [24][25][26][27][28][29][30][31] . NMPs are first observed in mouse embryos at about E8.0 near the node and caudal lateral epiblast lying on each side of the primitive streak [32][33][34] .…”

Section: Identification Of Ra-regulated Epigenetic Marks and Rares Nementioning

confidence: 99%

Discovery of genes required for body axis and limb formation by global identification of retinoic acid regulated epigenetic marks

Berenguer

Meyer

Yin

et al. 2019

Preprint

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Identification of target genes that mediate required functions downstream of transcription factors is hampered by the large number of genes whose expression changes when the factor is removed from a specific tissue and the numerous binding sites for the factor in the genome. Retinoic acid (RA) regulates transcription via RA receptors bound to RA response elements (RAREs) of which there are thousands in vertebrate genomes. Here, we combined ChIP-seq for epigenetic marks and RNA-seq on trunk tissue from wild-type and Aldh1a2-/-embryos lacking RA synthesis that exhibit body axis and forelimb defects. We identified a relatively small number of genes with altered expression when RA is missing that also have nearby RA-regulated deposition of H3K27ac (gene activation mark) or H3K27me3 (gene repression mark) associated with conserved RAREs, suggesting they have important downstream functions. RA-regulated epigenetic marks were identified near RA target genes already known to be required for body axis and limb formation, thus validating our approach, plus many other candidate RA target genes were found. Nr2f1, Nr2f2, Meis1, and Meis2 gene family members were identified by our approach, and double knockouts of each family demonstrated previously unknown requirements for body axis and/or limb formation. These findings demonstrate that our method for identifying RA-regulated epigenetic marks can be used to discover genes important for development.

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“…T-ChIP was performed from 2.5 × 10 7 mesodermal cells differentiated in vitro at day 4 of the differentiation protocol using an a-T antibody (5 lg, Santa Cruz, sc-17743). The ChIP protocol was performed according to [55]. ChIP DNA libraries (one biological replicate per genotype) were generated using the TruSeq ChIP Sample Preparation Kit (Illumina), according to manufacturer's instructions, with minor adjustments.…”

Section: Chip-seqmentioning

confidence: 99%

BRACHYURY directs histone acetylation to target loci during mesoderm development

et al. 2017

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T-box transcription factors play essential roles in multiple aspects of vertebrate development. Here, we show that cooperative function of BRACHYURY (T) with histone-modifying enzymes is essential for mouse embryogenesis. A single point mutation (T) results in decreased histone 3 lysine 27 acetylation (H3K27ac) at T target sites, including the locus, suggesting that T autoregulates the maintenance of its expression and functions by recruiting permissive chromatin modifications to putative enhancers during mesoderm specification. Our data indicate that T mediates H3K27ac recruitment through a physical interaction with p300. In addition, we determine that T plays a prominent role in the specification of hematopoietic and endothelial cell types. Hematopoietic and endothelial gene expression programs are disrupted in mutant embryos, leading to a defect in the differentiation of hematopoietic progenitors. We show that this role of T is mediated, at least in part, through activation of a distal enhancer.

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Antagonistic Activities of Sox2 and Brachyury Control the Fate Choice of Neuro-Mesodermal Progenitors

Cited by 151 publications

References 63 publications

Mechanics regulate human embryonic stem cell self-organization to specify mesoderm

Mechanics regulate human embryonic stem cell self-organization to specify mesoderm

Discovery of genes required for body axis and limb formation by global identification of retinoic acid regulated epigenetic marks

BRACHYURY directs histone acetylation to target loci during mesoderm development

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