Canonical WNT signaling-dependent gating of MYC requires a noncanonical CTCF function at a distal binding site

Ilyas Chachoua, Ilias Tzelepis, Hao Dai, Jia Pei Lim, Anna Lewandowska-Ronnegren, Felipe Beccaria Casagrande, Shuangyang Wu, Johanna Vestlund, Carolina Diettrich Mallet de Lima, Deeksha Bhartiya, Barbara A. Scholz, Mirco Martino, Rashid Mehmood and Anita Göndör ()
Additional contact information
Ilyas Chachoua: Karolinska Institutet
Ilias Tzelepis: Karolinska Institutet
Hao Dai: Karolinska Institutet
Jia Pei Lim: Karolinska Institutet
Anna Lewandowska-Ronnegren: Karolinska Institutet
Felipe Beccaria Casagrande: Karolinska Institutet
Shuangyang Wu: Karolinska Institutet
Johanna Vestlund: Karolinska Institutet
Carolina Diettrich Mallet de Lima: Karolinska Institutet
Deeksha Bhartiya: Karolinska Institutet
Barbara A. Scholz: Karolinska Institutet
Mirco Martino: Karolinska Institutet
Rashid Mehmood: Karolinska Institutet
Anita Göndör: Karolinska Institutet

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-021-27868-3

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