SummaryThe determination of long non-coding RNA (lncRNA) function is a major challenge in RNA biology with applications to basic, translational, and medical research. We developed BigHorn to computationally infer lncRNA-DNA interactions that mediate transcription and chromatin-remodeling factor activity. Its accurate inference enabled the identification of lncRNAs that coordinately regulate both the transcriptional and post-transcriptional processing of their targets. These lncRNAs may act as molecular chaperones, regulating the stability and translation of mRNAs they helped transcribe, leading to tightly coupled expression profiles. Our analysis suggests that lncRNAs regulate cancer genes across tumor contexts... More
SummaryThe determination of long non-coding RNA (lncRNA) function is a major challenge in RNA biology with applications to basic, translational, and medical research. We developed BigHorn to computationally infer lncRNA-DNA interactions that mediate transcription and chromatin-remodeling factor activity. Its accurate inference enabled the identification of lncRNAs that coordinately regulate both the transcriptional and post-transcriptional processing of their targets. These lncRNAs may act as molecular chaperones, regulating the stability and translation of mRNAs they helped transcribe, leading to tightly coupled expression profiles. Our analysis suggests that lncRNAs regulate cancer genes across tumor contexts, thus propagating the effects of non-coding alterations to effectively dysregulate cancer programs. As a proof of principle, we studied the regulation of DICER1 , a cancer gene that plays a key role in microRNA biogenesis, by the lncRNA ZFAS1 . We showed that ZFAS1 helps activate DICER1 transcription and block its mRNA degradation to phenomimic DICER1 and regulate its target microRNAs.Graphical abstractHighlights Elastic motifs improved lncRNA-DNA binding site inference lncRNAs can coordinately regulate the transcription and processing of their targets Coordinated regulation produces tight lncRNA-target couplings ZFAS1 activates DICER1 transcription and blocks the degradation of its mRNALong non-coding RNAs are abundant and dysregulated in cancers, but their functions are largely unknown. Chiu et al. developed intelligent methods to infer their function, revealing that these poorly studied genes regulate multiple gene processing steps to coordinately and tightly control cancer genes, establishing them as drivers of cancer progression.
