The WNT-dependent gating of MYC requires non-canonical functions of a distal CTCF binding site

Abnormal WNT signaling increases MYC expression in colon cancer cells in part via oncogenic super-enhancer-(OSE)-mediated gating of the active MYC to the nuclear pore in a poorly understood process. We show here that that the principal tenet of the WNT-regulated MYC gating, facilitated nuclear export of the MYC mRNA, converged on a single CTCF binding site (CTCFBS) within the OSE to confer increased growth advantage. To achieve this, the CTCFBS directed in a stepwise manner the WNT-dependent trafficking of the entire OSE to the nuclear pore from intra-nucleoplasmic positions. Once the OSE reached a perinuclear position, triggered by CTCFBS-mediated CCAT1 eRNA activation, its final stretch (<1micrometer) to the nuclear pore required the recruitment of AHCTF1, a key nucleoporin, to the CTCFBS. Thus, a novel WNT-CTCF-eRNA circuit converges on the ability of the OSE to promote pathological cell growth by coordinating the trafficking of MYC within the 3D nuclear architecture.