12), which has an instructive role in establishing extrusion-mediated structures that are visible in Hi-C 14. The predominant barrier to loop extrusion in vertebrates is CTCF (ref. The extrusion process is hypothesized to form progressively larger loops until cohesin encounters a barrier and/or is released by Wapl (refs. Structures that emerge through loop extrusion are detected by Hi-C experiments. On the basis of in vivo, in silico and in vitro data, we conclude that distinct loop extrusion barriers shape the three-dimensional genome.Įukaryotic genomes are folded into loops that are generated by structural maintenance of chromosomes (SMC) proteins, including cohesin and condensin complexes (reviewed previously 13). These findings raise the possibility that cohesin can arrive by loop extrusion at MCMs, which determine the genomic sites at which sister chromatid cohesion is established. Notably, chimeric yeast MCMs that contain a cohesin-interaction motif from human MCM3 induce cohesin pausing, indicating that MCMs are ‘active’ barriers with binding sites. Single-molecule imaging shows that MCMs are physical barriers that frequently constrain cohesin translocation in vitro.

Simulations suggest that MCMs are abundant, randomly positioned and partially permeable barriers. This effect extends to HCT116 cells, in which MCMs affect the number of CTCF-anchored loops and gene expression. Single-nucleus Hi-C (high-resolution chromosome conformation capture) of mouse zygotes reveals that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, which suggests that loop extrusion is impeded before reaching CTCF. Here we show that the minichromosome maintenance (MCM) complex is a barrier that restricts loop extrusion in G1 phase. Little is known about whether loop extrusion is impeded by DNA-bound machines. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered 6, 7, 8, 9, 10, 11, 12. Eukaryotic genomes are compacted into loops and topologically associating domains (TADs) 1, 2, 3, which contribute to transcription, recombination and genomic stability 4, 5.

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