Abstract
Enhancer (ENH)-associated long noncoding RNAs (lncRNA) are a peculiar class of RNAs produced by transcriptionally active ENHs, owning potential gene-regulatory function. Here, we characterized RAIN, a novel ENH-associated lncRNA. Analysis of RAIN expression in a retrospective cohort of human thyroid cancers showed that the expression of this lncRNA is restricted to cancer cells and strongly correlates with the expression of the cancer-promoting transcription factor RUNX2. We showed that RAIN, serving as a cis-regulatory element, promotes RUNX2 expression by two mechanisms. Binding WDR5 and facilitating its localization on the RUNX2 promoter, RAIN modifies the transcriptional status of the RUNX2 locus facilitating transcription initiation. In parallel, RAIN acts as decoy for negative elongation factor complex, restraining its inhibitory function on transcription elongation. In both thyroid and breast cancer cells, RAIN promotes oncogenic features. Using RNA-sequencing profiling, we showed that RAIN orchestrates the expression of a network of cancer-promoting transcription regulators, suggesting that RAIN affects cancer cell phenotype by coordinating the expression of a complex transcriptional network. IMPLICATIONS: Our data contribute to understand lncRNA function in gene regulation and to consolidate their role in cancer.
Highlights
IntroductionMutations in key coding genes alter cellular homeostasis and drive acquisition of malignant traits [1]
Similar to RUNX2, which shows two major Nterminal isoforms transcribed from two alternative promoters, RAIN presents two different 50-ends transcribed from two alternative starting sites located within RUNX2 ENH10 and ENH11, respectively, at 228.550 bp and 233.800 bp from the RUNX2 P2 promoter (Fig. 1A)
The two alternative 30-ends only differ in length, with the long RAIN isoforms exceeding of 3,010 bp the short ones
Summary
Mutations in key coding genes alter cellular homeostasis and drive acquisition of malignant traits [1]. Protein-coding sequences account for less than 2% of the entire genome, and genome-wide analyses have extensively documented the existence of functional mutations within noncoding regions in cancer [2]. The massive transcription activity of the noncoding genome is one of the most unexpected findings of the genomic era [3]. More than 60% of DNA is transcribed into noncoding RNA, whose major function is to control the expression of protein-coding genes at many levels. Long noncoding RNAs (lncRNA) are a class of noncoding transcripts defined by length greater than 200 nt and similarities to protein-coding genes including transcription mediated by RNA polymerase II (RNA-PolII) and multiple exons organization [4]
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