ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesin(STAG1) from WAPL

Eukaryotic genomes are folded into loops. It is thought that these are formed by cohesin complexes via extrusion, either until loop expansion is arrested by CTCF or until cohesin is removed from DNA by WAPL. Although WAPL limits cohesin’s chromatin residence time to minutes, it has been reported that some loops exist for hours. How these loops can persist is unknown. We show that during G1-phase, mammalian cells contain acetylated cohesin(STAG1) which binds chromatin for hours, whereas cohesin(STAG2) binds chromatin for minutes. Our results indicate that CTCF and the acetyltransferase ESCO1 protect a subset of cohesin(STAG1) complexes from WAPL, thereby enable formation of long and presumably long-lived loops, and that ESCO1, like CTCF, contributes to boundary formation in chromatin looping. Our data are consistent with a model of nested loop extrusion, in which acetylated cohesin(STAG1) forms stable loops between CTCF sites, demarcating the boundaries of more transient cohesin(STAG2) extrusion activity.