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  Hypoxia induces a transcriptional early primitive streak signature in pluripotent cells enhancing spontaneous elongation and lineage representation in gastruloids

López-Anguita, N., Gassaloglu, S. I., Stötzel, M., Typou, M., Virta, I., Hetzel, S., et al. (2021). Hypoxia induces a transcriptional early primitive streak signature in pluripotent cells enhancing spontaneous elongation and lineage representation in gastruloids. BioRxiv. doi:10.1101/2021.07.21.452906.

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López-Anguita_Preprint2021.pdf (Preprint), 24MB
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López-Anguita, Natalia1, Author           
Gassaloglu, Seher Ipek2, Author           
Stötzel, Maximilian1, Author           
Typou, Marina1, Author           
Virta, Iiris1, Author           
Hetzel, Sara3, Author           
Buschow, Rene4, Author           
Koksal, Burak , Author
Atilla, Derya , Author
Maitschke-Rajasekharan, Ronald1, Author           
Chen, Rui, Author
Mattei, Alexandra L.3, Author           
Bedzhov, Ivan , Author
Meierhofer, David5, Author           
Meissner, Alexander3, Author           
Veenvliet, Jesse V.2, Author           
Bulut-Karslioglu, Aydan1, Author           
Affiliations:
1Stem Cell Chromatin (Aydan Bulut-Karslioglu), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014185              
2Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
3Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
4Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              
5Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              

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 Abstract: The cellular microenvironment together with intrinsic regulators shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and appear to benefit from hypoxic culture in vitro. Yet, components of the hypoxia response and how their interplay impacts stem cell transcriptional networks and lineage choices remain poorly understood. Here we investigated the molecular effects of acute and prolonged hypoxia on distinct embryonic and extraembryonic stem cell types as well as the functional impact on differentiation potential. We find a temporal and cell type-specific transcriptional response including an early primitive streak signature in hypoxic embryonic stem (ES) cells. Using a 3D gastruloid differentiation model, we show that hypoxia-induced T expression enables symmetry breaking and axial elongation in the absence of exogenous WNT activation. Importantly, hypoxia also modulates T levels in conventional gastruloids and enhances representation of endodermal and neural markers. Mechanistically, we identify Hif1α as a central factor that mediates the transcriptional response to hypoxia in balance with epigenetic and metabolic rewiring. Our findings directly link the microenvironment to stem cell function and provide a rationale supportive of applying physiological conditions in models of embryo development.

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Language(s): eng - English
 Dates: 2021-07-22
 Publication Status: Published online
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 Identifiers: DOI: 10.1101/2021.07.21.452906
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Title: BioRxiv
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