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

Ilyas Chachoua,Barbara A Scholz,Rashid Mehmood,Jia Pei Lim,Shuangyang Wu,Hao Dai,Deeksha Bhartiya,Felipe Beccaria Casagrande,Carolina Diettrich Mallet De Lima,Ilias Tzelepis,Mirco Martino,Anita Göndör,Johanna Vestlund,Anna Lewandowska-Ronnegren

doi:10.1038/s41467-021-27868-3

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.

Highlights

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
It identifies a single CTCF binding site (CTCFBS) within the OSE as a key target for WNT signaling to increase the nuclear export rate of MYC mRNAs, uncovering a WNT/ß-cateninAHCTF1-CTCF-eRNA circuit
This feature is intimately linked with the CTCFBS-dependent recruitment of AHCTF1, which is a key mediator of the increased MYC mRNA export rate[7]

Summary

Introduction

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. CTCF has been described as a master regulator of the genome, attributed to a range of pivotal processes[8] These include the organization of chromatin insulators, boundaries[9], enhancer–gene interactions via the cohesin complex[10], as well as the mediation of the rhythmic recruitment of active circadian genes to the lamina for subsequent repression[11]. It binds to a region within the OSE that shows physical proximity with MYC in colon cancer cells[7], and third, CTCF is linked with long-range regulation of MYC expression[12,13]. It has been argued that OSE-MYC interactions are facilitated by the CCAT1 eRNA when complexed with CTCF14,15

Methods

Results

Conclusion