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Epigenetic regulator function through mouse gastrulation

Author

Listed:
  • Stefanie Grosswendt

    (Max Planck Institute for Molecular Genetics)

  • Helene Kretzmer

    (Max Planck Institute for Molecular Genetics)

  • Zachary D. Smith

    (Broad Institute of MIT and Harvard
    Harvard University
    Harvard University)

  • Abhishek Sampath Kumar

    (Max Planck Institute for Molecular Genetics)

  • Sara Hetzel

    (Max Planck Institute for Molecular Genetics)

  • Lars Wittler

    (Max Planck Institute for Molecular Genetics)

  • Sven Klages

    (Max Planck Institute for Molecular Genetics)

  • Bernd Timmermann

    (Max Planck Institute for Molecular Genetics)

  • Shankar Mukherji

    (Washington University in St Louis)

  • Alexander Meissner

    (Max Planck Institute for Molecular Genetics
    Broad Institute of MIT and Harvard
    Harvard University)

Abstract

During ontogeny, proliferating cells become restricted in their fate through the combined action of cell-type-specific transcription factors and ubiquitous epigenetic machinery, which recognizes universally available histone residues or nucleotides in a context-dependent manner1,2. The molecular functions of these regulators are generally well understood, but assigning direct developmental roles to them is hampered by complex mutant phenotypes that often emerge after gastrulation3,4. Single-cell RNA sequencing and analytical approaches have explored this highly conserved, dynamic period across numerous model organisms5–8, including mouse9–18. Here we advance these strategies using a combined zygotic perturbation and single-cell RNA-sequencing platform in which many mutant mouse embryos can be assayed simultaneously, recovering robust morphological and transcriptional information across a panel of ten essential regulators. Deeper analysis of central Polycomb repressive complex (PRC) 1 and 2 components indicates substantial cooperativity, but distinguishes a dominant role for PRC2 in restricting the germline. Moreover, PRC mutant phenotypes emerge after gross epigenetic and transcriptional changes within the initial conceptus prior to gastrulation. Our experimental framework may eventually lead to a fully quantitative view of how cellular diversity emerges using an identical genetic template and from a single totipotent cell.

Suggested Citation

  • Stefanie Grosswendt & Helene Kretzmer & Zachary D. Smith & Abhishek Sampath Kumar & Sara Hetzel & Lars Wittler & Sven Klages & Bernd Timmermann & Shankar Mukherji & Alexander Meissner, 2020. "Epigenetic regulator function through mouse gastrulation," Nature, Nature, vol. 584(7819), pages 102-108, August.
  • Handle: RePEc:nat:nature:v:584:y:2020:i:7819:d:10.1038_s41586-020-2552-x
    DOI: 10.1038/s41586-020-2552-x
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    Cited by:

    1. Andrea Lauria & Guohua Meng & Valentina Proserpio & Stefania Rapelli & Mara Maldotti & Isabelle Laurence Polignano & Francesca Anselmi & Danny Incarnato & Anna Krepelova & Daniela Donna & Chiara Levra, 2023. "DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Simon Andrews & Christel Krueger & Maravillas Mellado-Lopez & Myriam Hemberger & Wendy Dean & Vicente Perez-Garcia & Courtney W. Hanna, 2023. "Mechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Qing Li & Jiansen Lu & Xidi Yin & Yunjian Chang & Chao Wang & Meng Yan & Li Feng & Yanbo Cheng & Yun Gao & Beiying Xu & Yao Zhang & Yingyi Wang & Guizhong Cui & Luang Xu & Yidi Sun & Rong Zeng & Yixue, 2023. "Base editing-mediated one-step inactivation of the Dnmt gene family reveals critical roles of DNA methylation during mouse gastrulation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Kentaro Mochizuki & Jafar Sharif & Kenjiro Shirane & Kousuke Uranishi & Aaron B. Bogutz & Sanne M. Janssen & Ayumu Suzuki & Akihiko Okuda & Haruhiko Koseki & Matthew C. Lorincz, 2021. "Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Chet H. Loh & Siebe Genesen & Matteo Perino & Magnus R. Bark & Gert Jan C. Veenstra, 2021. "Loss of PRC2 subunits primes lineage choice during exit of pluripotency," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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