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EMBO J. 2017 Dec 15;36(24):3600-3618. doi: 10.15252/embj.201798083. Epub 2017 Dec 7.

A mechanism of cohesin-dependent loop extrusion organizes zygotic genome architecture.

Author information

1
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria.
2
Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA.
3
Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
4
Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
5
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
6
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
7
Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA leonid@mit.edu kikue.tachibana@imba.oeaw.ac.at.
8
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria leonid@mit.edu kikue.tachibana@imba.oeaw.ac.at.

Abstract

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.

KEYWORDS:

chromatin structure; cohesin; loop extrusion; reprogramming; zygote

PMID:
29217590
PMCID:
PMC5730859
DOI:
10.15252/embj.201798083
[Indexed for MEDLINE]
Free PMC Article

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