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. Examination of CTCF binding in D3, E4 and WT. All the cell line is HCT-116. D3 and E4 are two clones of CTCF mutation.