PT  - JOURNAL ARTICLE
AU  - Johanna Gassler
AU  - Hugo B. Brandão
AU  - Maxim Imakaev
AU  - Ilya M. Flyamer
AU  - Sabrina Ladstätter
AU  - Wendy A. Bickmore
AU  - Jan-Michael Peters
AU  - Leonid A. Mirny
AU  - Kikuë Tachibana-Konwalski
TI  - A Mechanism of Cohesin-Dependent Loop Extrusion Organizes Zygotic Genome Architecture
AID  - 10.1101/177766
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 177766
4099  - http://biorxiv.org/content/early/2017/08/17/177766.short
4100  - http://biorxiv.org/content/early/2017/08/17/177766.full
AB  - Fertilization 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