Epigenetic regulator function through mouse gastrulation

Stefanie Grosswendt, Helene Kretzmer, Zachary D. Smith, Abhishek Sampath Kumar, Sara Hetzel, Lars Wittler, Sven Klages, Bernd Timmermann, Shankar Mukherji and Alexander Meissner ()
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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
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

Nature, 2020, vol. 584, issue 7819, 102-108

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2552-x

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