De novo formation of cis-regulatory contacts in the absence of NIPBL-driven chromatin loop extrusion

NIPBL promotes chromatin loop extrusion by the cohesin complex until it stalls at convergently oriented CTCF sites, forming structural loops. In contrast, a large fraction of loops connecting cis-regulatory elements (CREs) can be maintained in the absence of cohesin. However, whether de novo establishment of CRE loops requires loop extrusion remains unclear. To address this question, we characterized the formation of structural and CRE loops during the mitosis-to-G1-phase transition in the absence of NIPBL. Structural loop formation was impaired proportionally to loop length. Computational modeling supports these observations, suggesting that NIPBL enhances cohesin extrusion beyond NIPBL’s known loading function. Importantly the majority of CRE loops, regardless of length, was established independently of loop extrusion. While globally gene activation showed little impairment, NIPBL loss delayed the formation of CRE loops involving weak enhancers. Collectively, our findings reveal that post-mitotic establishment of regulatory contacts and gene transcription can occur independently of chromatin loop extrusion.