Canonical WNT signaling-dependent gating of MYC requires a noncanonical CTCF function at a distal binding site.
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Chachoua I, Tzelepis I, Dai H, Lim JP, Lewandowska-Ronnegren A, Casagrande FB, Wu S, Vestlund J, Mallet de Lima CD, Bhartiya D, Scholz BA, Martino M, Mehmood R, Göndör A
Nat Commun 13 (1) 204 [2022-01-11; online 2022-01-11]
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 the principal tenet of the WNT-regulated MYC gating, facilitating nuclear export of the MYC mRNA, is regulated by a CTCF binding site (CTCFBS) within the OSE to confer growth advantage in HCT-116 cells. To achieve this, the CTCFBS directs the WNT-dependent trafficking of the OSE to the nuclear pore from intra-nucleoplasmic positions in a stepwise manner. Once the OSE reaches a peripheral position, which is triggered by a CTCFBS-mediated CCAT1 eRNA activation, its final stretch (≤0.7 μm) to the nuclear pore requires the recruitment of AHCTF1, a key nucleoporin, to the CTCFBS. Thus, a WNT/ß-catenin-AHCTF1-CTCF-eRNA circuit enables the OSE to promote pathological cell growth by coordinating the trafficking of the active MYC gene within the 3D nuclear architecture.
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PubMed 35017527
DOI 10.1038/s41467-021-27868-3
Crossref 10.1038/s41467-021-27868-3
pii: 10.1038/s41467-021-27868-3
pmc: PMC8752836