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A Mechanism of Cohesin-Dependent Loop Extrusion Organizes Zygotic Genome Architecture

Johanna Gassler, Hugo B. Brandão, Maxim Imakaev, Ilya M. Flyamer, Sabrina Ladstätter, Wendy A. Bickmore, Jan-Michael Peters, Leonid A. Mirny, Kikuë Tachibana-Konwalski
doi: https://doi.org/10.1101/177766
Johanna Gassler
1Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr Bohr-Gasse 3, 1030 Vienna, Austria
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Hugo B. Brandão
2Harvard Program in Biophysics, Harvard University, Cambridge, Massachusetts 02138, USA
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Maxim Imakaev
3Institute for Medical Engineering and Science, Massachusetts Institute of Technology(MIT), Cambridge, Massachusetts 02139, USA
4Department of Physics, MIT, Cambridge, Massachusetts 02139, USA
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Ilya M. Flyamer
5MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh EH4 2XU, UK
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Sabrina Ladstätter
1Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr Bohr-Gasse 3, 1030 Vienna, Austria
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Wendy A. Bickmore
5MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh EH4 2XU, UK
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Jan-Michael Peters
6Institute of Molecular Pathology (IMP), VBC, Vienna Biocenter 1, 1030 Vienna, Austria
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Leonid A. Mirny
2Harvard Program in Biophysics, Harvard University, Cambridge, Massachusetts 02138, USA
3Institute for Medical Engineering and Science, Massachusetts Institute of Technology(MIT), Cambridge, Massachusetts 02139, USA
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  • For correspondence: kikue.tachibana@imba.oeaw.ac.at leonid@mit.edu
Kikuë Tachibana-Konwalski
1Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr Bohr-Gasse 3, 1030 Vienna, Austria
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  • For correspondence: kikue.tachibana@imba.oeaw.ac.at leonid@mit.edu
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SUMMARY

Fertilization triggers assembly of higher-order chromatin structure from a naïve genome to generate a totipotent embryo. Chromatin loops and domains are detected in mouse zygotes by single-nucleus Hi-C (snHi-C) but not bulk Hi-C. We resolve this discrepancy by investigating whether a mechanism of cohesin-dependent loop extrusion generates zygotic chromatin conformations. Using snHi-C of mouse knockout embryos, we demonstrate that the zygotic genome folds into loops and domains that depend on Scc1-cohesin and are regulated in size by Wapl. Remarkably, we discovered distinct effects on maternal and paternal chromatin loop sizes, likely reflecting loop extrusion dynamics and epigenetic reprogramming. Polymer simulations based on snHi-C are consistent with a model where cohesin locally compacts chromatin and thus restricts inter-chromosomal interactions by active loop extrusion, whose processivity is controlled by Wapl. Our simulations and experimental data provide evidence that cohesin-dependent loop extrusion organizes mammalian genomes over multiple scales from the one-cell embryo onwards.

Highlights

  • Zygotic genomes are organized into cohesin-dependent chromatin loops and TADs

  • Loop extrusion leads to different loop strengths in maternal and paternal genomes

  • Cohesin restricts inter-chromosomal interactions by altering chromosome surface area

  • Loop extrusion organizes chromatin at multiple genomic scales

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted August 17, 2017.
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A Mechanism of Cohesin-Dependent Loop Extrusion Organizes Zygotic Genome Architecture
Johanna Gassler, Hugo B. Brandão, Maxim Imakaev, Ilya M. Flyamer, Sabrina Ladstätter, Wendy A. Bickmore, Jan-Michael Peters, Leonid A. Mirny, Kikuë Tachibana-Konwalski
bioRxiv 177766; doi: https://doi.org/10.1101/177766
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A Mechanism of Cohesin-Dependent Loop Extrusion Organizes Zygotic Genome Architecture
Johanna Gassler, Hugo B. Brandão, Maxim Imakaev, Ilya M. Flyamer, Sabrina Ladstätter, Wendy A. Bickmore, Jan-Michael Peters, Leonid A. Mirny, Kikuë Tachibana-Konwalski
bioRxiv 177766; doi: https://doi.org/10.1101/177766

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