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

Abstract

Fertilization triggers assembly of higher-order chromatin structure from a naive 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.\n\nHighlightsO_LIZygotic genomes are organized into cohesin-dependent chromatin loops and TADs\nC_LIO_LILoop extrusion leads to different loop strengths in maternal and paternal genomes\nC_LIO_LICohesin restricts inter-chromosomal interactions by altering chromosome surface area\nC_LIO_LILoop extrusion organizes chromatin at multiple genomic scales\nC_LI