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

Johanna Gassler,Kikuë Tachibana,Leonid A Mirny,Maxim Imakaev,Hugo B Brandão,Ilya M Flyamer,Wendy A Bickmore,Jan‐Michael Peters,Sabrina Ladstätter

doi:10.15252/embj.201798083

Johanna Gassler, Kikuë Tachibana + Show 7 more

Open Access

https://doi.org/10.15252/embj.201798083

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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.

Highlights

Fertilization triggers assembly of higher-order chromatin structure from a condensed maternal and a naïve paternal genome to generate a totipotent embryo
Using single-nucleus Hi-C (snHi-C), we recently found that mouse zygotic genomes are organized into chromatin loops, topologically associating domains (TADs), and compartments as early as G1 phase (Flyamer et al, 2017; Fig 2A)
More recent studies have shown that cohesin colocalizes with CTCF and is associated with TADs and chromatin loops (Wendt et al, 2008; Dixon et al, 2012; Nora et al, 2012; Phillips-Cremins et al, 2013; Rao et al, 2014; Hansen et al, 2017; Nora et al, 2017), which implicated cohesin as a regulator of intra-chromosomal structure

Summary

Introduction

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 unclear when and how embryonic chromatin conformations are assembled. 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. Our simulations and experimental data provide evidence that cohesin-dependent loop extrusion organizes mammalian genomes over multiple scales from the onecell embryo onward

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Conclusion