Journal
EMBO JOURNAL
Volume 36, Issue 24, Pages 3600-3618Publisher
WILEY
DOI: 10.15252/embj.201798083
Keywords
chromatin structure; cohesin; loop extrusion; reprogramming; zygote
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Funding
- Austrian Science Fund (FWF) [W1238-B20]
- European Research Council
- Natural Sciences and Engineering Research Council of Canada
- Darwin Trust of Edinburgh
- UK Medical Research Council
- Austrian Academy of Sciences
- ChromHeritance grant [ERC-StG-336460]
- National Institute of Health [R01 GM114190, U54 DK107980]
- National Science Foundation [1504942]
- MRC [MC_PC_U127527202] Funding Source: UKRI
- Austrian Science Fund (FWF) [W1238] Funding Source: Austrian Science Fund (FWF)
- Medical Research Council [MC_PC_U127527202] Funding Source: researchfish
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Fertilization triggers assembly of higher-order chromatin structure from a condensed maternal and a naive 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.
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