Activity-induced gene expression and long-range enhancer-promoter contacts in cohesin-deficient neurons

Cohesin and CTCF are major drivers of 3D genome organization. Even though human mutations underscore the importance of cohesin and CTCF for neurodevelopment, their role in neurons is only just beginning to be addressed. Here we conditionally ablate Rad21 in cortical neurons, revealing a prominent role for cohesin in the expression of genes that facilitate neuronal maturation, homeostasis, and activation. In agreement with recent reports, activity-dependent genes were downregulated at baseline. However, in contrast to current models that attribute impaired activity-dependent gene expression to a role for cohesin and CTCF in anchoring enhancer-promoter contacts, we show that nearly all activity-dependent genes remain inducible in the absence of cohesin. While CTCF-based chromatin loops were substantially weakened, long-range contacts still formed robustly between activity-dependent enhancers and their target immediate early gene promoters. We suggest a model where neuronal cohesin facilitates the precise level of activity-dependent gene expression, rather than inducibility per se, and where inducibility of activity-dependent gene expression is linked to cohesin-independent enhancer-promoter contacts. These data expand our understanding of the importance of cohesin-independent enhancer-promoter contacts in regulating gene expression.