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Inappropriate activation of  c-Myc  ( MYC ) gene expression by the Wnt/ß-catenin signaling pathway is required for colorectal carcinogenesis. The elevated MYC levels in colon cancer cells are attributed in part to ß-catenin/TCF4 transcription complexes that are assembled at proximal Wnt/ß-catenin responsive enhancers (WREs). Recent studies suggest that additional WREs that control  MYC  expression reside far upstream of the  MYC  transcription start site. Here, I report the characterization of five novel WREs that localize to a region over 400 kb upstream from  MYC . These WREs harbor nucleosomes with post-translational histone modifications that demarcate enhancer and gene promoter regions. Using quantitative chromatin conformation capture, I show that the distal WREs are aligned with the  MYC  promoter through large chromatin loops. The chromatin loops are not restricted to colon cancer cells, but are also found in kidney epithelial and lung fibroblast cell lines that lack de-regulated Wnt signaling and nuclear ß-catenin/TCF4 complexes. While each chromatin loop is detected in quiescent cells, the positioning of three of the five distal enhancers with the  MYC  promoter is induced by serum mitogens. These findings suggest that the architecture of the  MYC  promoter is comprised of distal elements that are juxtaposed through large chromatin loops and that ß-catenin/TCF4 complexes utilize this conformation to activate  MYC  expression in colon cancer cells.

Multiple Wnt/ß-Catenin Responsive Enhancers Align with the MYC Promoter through Long-Range Chromatin Loops