Coordinated regulation by lncRNAs results in tight lncRNA-target couplings

Abstract

The 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.

Keywords: BigHorn; CRISPRi; ChIRP; DICER1; ZFAS1; coordinated regulation; elastic motif; functional genomics; lncRNA; mechanistic model; miRNA biogenesis; multiomics; target prediction; tight coupling.