Genome-wide in vivo dynamics of cohesin-mediated loop extrusion and its role in transcription activation

Abstract

The organization of the genome in three-dimensional space is highly dynamic, yet how these dynamics are regulated and the role they play in genome function is poorly understood. Here, we utilized acute depletion of NIPBL to characterize the role of cohesin-mediated loop extrusion in vivo. Using this approach, we found that many chromatin loops are rapidly diminished upon loss of NIBPL, consistent with recent single locus imaging studies showing that chromatin loops are transient. However, we also identified cohesin-dependent chromatin loops that are associated with distinct chromatin states and may be "long-lived", given that they require NIPBL for their establishment upon mitotic exit, but are persistent when NIPBL is depleted from interphase cells. In addition to the reformation of 3D genome structures, mitotic exit coincides with widespread transcriptional activation. We found that NIPBL is essential for establishing the expression of lineage-defining genes during the M-G1 transition but has diminished impact on the steady-state maintenance of their expression. At genes sensitive to its depletion, NIPBL supports a unique local genome organization defined by greater spatial proximity to nearby super-enhancers and weaker transcription start site insulation of genomic contacts. Overall, we show that NIPBL-mediated loop extrusion is critical to genome organization and transcription regulation in vivo.