A functional SNP regulates E-cadherin expression by dynamically remodeling the 3D structure of a promoter-associated non-coding RNA transcript

Transcription of E-cadherin, a tumor suppressor which plays critical roles in cell adhesion and the epithelial-mesenchymal transition, is regulated by a promoter-associated non-coding transcript. This RNA includes a functional C/A single nucleotide polymorphism (SNP rs16260). The A-allele is linked to decreased transcriptional activity and increased prostate cancer risk. This single nucleotide change affects recruitment of an iso-miRNA and epigenetic enzymes to regulate the promoter, yet it is distant from the isomiR-binding site in both primary sequence and secondary structure, raising the question of how regulation occurs. Here we report the 3D NMR structure of the domain of 90 nucleotides within the paRNA which includes the SNP and the isomiR-binding site. We show that the A->C mutation alters the locally dynamic structure of the paRNA, revealing that the mutation regulates the E-cadherin promoter through its effect on RNA structure.