An Evolutionarily Conserved AU-Rich Element in the 3' Untranslated Region of a Transcript Misannotated as a Long Noncoding RNA Regulates RNA Stability.

One of the primary mechanisms of post-transcriptional gene regulation is the modulation of RNA stability. We recently discovered that , a transcript annotated as a long noncoding RNA (lncRNA), is transcriptionally regulated by FOXA1 and encodes a highly conserved small protein that localizes to the endoplasmic reticulum, hence renamed as (FOXA1-regulated conserved small protein). Here, we show that the endogenous transcript is rapidly degraded and rendered unstable as a result of 3'UTR-mediated degradation. Surprisingly, although the transcript is a canonical nonsense-mediated decay (NMD) and microRNA (miRNA) target, we found that it is not degraded by NMD or miRNAs. Targeted deletion of an evolutionarily conserved region in the 3'UTR using CRISPR/Cas9 significantly increased the stability of the transcript. Interestingly, this region requires the presence of an immediate downstream 55-nt-long sequence for transcript stability regulation. Functionally, colorectal cancer cells lacking this conserved region expressed from the endogenous locus displayed decreased proliferation and clonogenicity. These data demonstrate that the transcript is destabilized via conserved elements within its 3'UTR and emphasize the need to interrogate the function of a given 3'UTR in its native context.