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

• DOI: 10.15252/embj.201798083
• Publication Date: 2017-12-08T01:10:31Z
• Authors: Johanna Gassler; Hugo B Brandão; Maxim Imakaev; Ilya M Flyamer; Sabrina Ladstätter; Wendy A Bickmore; Jan‐Michael Peters; Leonid A Mirny; Kikuë Tachibana
• Keywords: Epigenomics; Male; 0301 basic medicine; zygote; 570; Chromosomal Proteins, Non-Histone; Zygote; cohesin; Cell Cycle Proteins; Article; Chromosomes; Gene Knockout Techniques; Mice; 03 medical and health sciences; Proto-Oncogene Proteins; Animals; Cohesins; chromatin structure; 0303 health sciences; loop extrusion; Genome; Cell Cycle; reprogramming; 500; Nuclear Proteins; Articles; Phosphoproteins; Chromatin; DNA-Binding Proteins; Mice, Inbred C57BL; Genomics & Functional Genomics; Epigenetics; Female; Carrier Proteins; Development & Differentiation

SUMMARYFertilization 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.HighlightsZygotic genomes are organized into cohesin-dependent chromatin loops and TADsLoop extrusion leads to different loop strengths in maternal and paternal genomesCohesin restricts inter-chromosomal interactions by altering chromosome surface areaLoop extrusion organizes chromatin at multiple genomic scales