Abstract
Long ncRNAs are often enriched in the nucleus and at chromatin, but whether their dissociation from chromatin is important for their role in transcription regulation is unclear. Here, we group long ncRNAs using epigenetic marks, expression and strength of chromosomal interactions; we find that long ncRNAs transcribed from loci engaged in strong long-range chromosomal interactions are less abundant at chromatin, suggesting the release from chromatin as a crucial functional aspect of long ncRNAs in transcription regulation of their target genes. To gain mechanistic insight into this, we functionally validate the long ncRNA A-ROD, which enhances DKK1 transcription via its nascent spliced released form. Our data provide evidence that the regulatory interaction requires dissociation of A-ROD from chromatin, with target specificity ensured within the pre-established chromosomal proximity. We propose that the post-transcriptional release of a subset of long ncRNAs from the chromatin-associated template plays an important role in their function as transcription regulators.
Highlights
Long ncRNAs are often enriched in the nucleus and at chromatin, but whether their dissociation from chromatin is important for their role in transcription regulation is unclear
We find that, among long ncRNAs actively expressed in MCF-7 breast-cancer cells, those transcribed from loci engaged in strong RNA polymerase II (Pol II)-dependent chromosomal interactions to target gene promoters are less enriched in the chromatin-associated RNA fraction
Here, we group long ncRNAs by epigenetic marks and find that around a quarter are engaged in strong long-range chromosomal interactions in MCF-7 cells
Summary
Long ncRNAs are often enriched in the nucleus and at chromatin, but whether their dissociation from chromatin is important for their role in transcription regulation is unclear. We find that, among long ncRNAs actively expressed in MCF-7 breast-cancer cells, those transcribed from loci engaged in strong RNA polymerase II (Pol II)-dependent chromosomal interactions to target gene promoters are less enriched in the chromatin-associated RNA fraction. Through functional analyses of the long ncRNA A-ROD (Activating Regulator of DKK1), we show that transcriptional enhancement of its target gene DKK1 is accompanied by an A-ROD-dependent recruitment of the general transcription factor EBP1 to the DKK1 promoter. The mechanistic insights gained from this study establish that dissociation of activating long ncRNAs from chromatin is necessary to mediate RNA-dependent regulation of their target gene expression, adding an important new mechanistic perspective to the functional repertoire of long ncRNAs. has been used to map enhancer-promoter interactions[31]. This set was further narrowed down to 4467 long ncRNAs with detectable expression in MCF-7 cells, used in all subsequent analyses (Fig. 1a, Supplementary Data 1, and Methods section)
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