The transcribed ultraconserved region uc.160+ enhances processing and A‐to‐I editing of the miR‐376 cluster: hypermethylation improves glioma prognosis

Transcribed ultraconserved regions (T‐UCRs) are noncoding RNAs derived from DNA sequences that are entirely conserved across species. Their expression is altered in many tumor types, and, although a role for T‐UCRs as regulators of gene expression has been proposed, their functions remain largely unknown. Herein, we describe the epigenetic silencing of the uc.160+ T‐UCR in gliomas and mechanistically define a novel RNA–RNA regulatory network in which uc.160+ modulates the biogenesis of several members of the miR‐376 cluster. This includes the positive regulation of primary microRNA (pri‐miRNA) cleavage and an enhanced A‐to‐I editing on its mature sequence. As a consequence, the expression of uc.160+ affects the downstream, miR‐376‐regulated genes, including the transcriptional coregulators RING1 and YY1‐binding protein (RYBP) and forkhead box P2 (FOXP2). Finally, we elucidate the clinical impact of our findings, showing that hypermethylation of the uc.160+ CpG island is an independent prognostic factor associated with better overall survival in lower‐grade gliomas, highlighting the importance of T‐UCRs in cancer pathophysiology. The transcribed ultraconserved region uc.160+ has been reported to be regulated by DNA methylation. Here, we describe that uc.160+ increases the biogenesis of the miR‐376 family through base‐pairing complementarity. The process includes enhanced pri‐miRNA processing and A‐to‐I editing. This represents a novel RNA–RNA regulatory network that acts in fine‐tuning the regulation of miR‐376 targets such as RYBP and FOXP2, and has an impact on glioma prognosis. Our study highlights the potential use of uc.160+ hypermethylation as a biomarker in patients with glioma.