A functional SNP regulates E-cadherin expression by dynamically remodeling the 3D structure of a promoter-associated non-coding RNA transcript. Issue 19 (16th October 2022)

• Record Type: Journal Article
• Authors: Sharma, Shrikant; Pisignano, Giuseppina; Merulla, Jessica; Catapano, Carlo V; Varani, Gabriele
• Is Part Of: Nucleic acids research. Volume 50:Issue 19(2022)
• Page Start: 11331
• Page End: 11343
• Publication Date: 2022-10-16
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkac875
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Transcription of E-cadherin, a tumor suppressor that plays critical roles in cell adhesion and the epithelial-mesenchymal transition, is regulated by a promoter-associated non-coding RNA (paRNA). The sense-oriented paRNA (S-paRNA) includes a functional C/A single nucleotide polymorphism (SNP rs16260). The A-allele leads to decreased transcriptional activity and increased prostate cancer risk. The polymorphic site is known to affect binding of a microRNA-guided Argonaute 1 (AGO1) complex and recruitment of chromatin-modifying enzymes to silence the promoter. Yet the SNP is distant from the microRNA-AGO1 binding domain in both primary sequence and secondary structure, raising the question of how regulation occurs. Here we report the 3D NMR structure of the 104-nucleotide domain of the S-paRNA that encompasses the SNP and the microRNA-binding site. We show that the A to C change alters the locally dynamic and metastable structure of the S-paRNA, revealing how the single nucleotide mutation regulates the E-cadherin promoter through its effect on the non-coding RNA structure.