Chromatin-release of the long ncRNA A-ROD is required for transcriptional activation of its target gene DKK1

Abstract

Long non-coding RNAs (ncRNAs) are involved in both positive and negative regulation of transcription. Long ncRNAs are often enriched in the nucleus and at chromatin but whether chromatin-release plays a functional role is unknown. Here, we used epigenetic marks, expression level and strength of chromatin interactions to group long ncRNAs and find that those engaged in strong chromatin interactions are less enriched at chromatin in MCF-7 cells, suggesting a functional involvement of chromatin-release of long ncRNAs in transcriptional regulation. To study this further, we identify the long ncRNA A-ROD, an activating regulator of the Wnt signaling inhibitor DKK1. We show that A-ROD enhances transcription elongation of DKK1 in an RNA-dependent manner and that A-ROD recruits EBP1 to the DKK1 promoter. Our data suggest that the activating function depends on the release of A-ROD from chromatin, and further identify a functional regulatory interaction mediated by A-ROD in the transcription activation of DKK1. We propose that the release of a subset of long ncRNAs is important for their function, adding a new mechanistic perspective to the subcellular localization of long ncRNAs.

Predictive models of subcellular localization of long RNAs

“…Regulated splicing can further assist in "releasing" the RNA from one compartment to another, allowing precise timing of its functional activity. For instance, a recent study has found that release from chromatin is essential for function of lncRNA A-ROD (Ntini et al 2018). For PCGs, regulated nuclear retention through regulation of splicing has been shown to orchestrate trans-lation and protein accumulation in several contexts (Ninomiya et al 2011;Mauger et al 2016;Naro et al 2017).…”