A mechanism of cohesin‐dependent loop extrusion organizes zygotic genome architecture

• Johanna Gassler ^[4] ; Hugo B Brandão ^[5] ; Maxim Imakaev ^[3] ; Ilya M Flyamer ^[1] ; Sabrina Ladstätter ^[4] ; Wendy A Bickmore ^[1] ; Jan‐Michael Peters ^[2] ; Leonid A Mirny ^[3] ; Kikuë Tachibana ^[4]
  1. [1] Medical Research Council Institute of Genetics and Molecular Medicine

     Medical Research Council Institute of Genetics and Molecular Medicine

     Reino Unido

     
  2. [2] Research Institute of Molecular Pathology

     Research Institute of Molecular Pathology

     Innere Stadt, Austria

     
  3. [3] Massachusetts Institute of Technology

     Massachusetts Institute of Technology

     City of Cambridge, Estados Unidos

     
  4. [4] Institute of Molecular Biotechnology

     Institute of Molecular Biotechnology

     Innere Stadt, Austria

     
  5. [5] 2 Harvard Graduate Program in Biophysics Harvard University Cambridge MA USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 24, 2017, págs. 3600-3618
• Idioma: inglés
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• Resumen

  • Fertilization triggers assembly of higher‐order chromatin structure from a condensed maternal and a naïve paternal genome to generate a totipotent embryo. Chromatin loops and domains have been detected in mouse zygotes by single‐nucleus Hi‐C (snHi‐C), but not bulk Hi‐C. It is therefore unclear when and how embryonic chromatin conformations are assembled. Here, we investigated whether a mechanism of cohesin‐dependent loop extrusion generates higher‐order chromatin structures within the one‐cell embryo. Using snHi‐C of mouse knockout embryos, we demonstrate that the zygotic genome folds into loops and domains that critically depend on Scc1‐cohesin and that are regulated in size and linear density by Wapl. Remarkably, we discovered distinct effects on maternal and paternal chromatin loop sizes, likely reflecting differences in loop extrusion dynamics and epigenetic reprogramming. Dynamic polymer models of chromosomes reproduce changes in snHi‐C, suggesting a mechanism where cohesin locally compacts chromatin 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 onward.