The lncRNA Firre functions as a rapid regulator of transcription from a distance [ChIP-Seq]

There are currently over 16,000 long-noncoding RNAs (lncRNAs) annotated in mammalian genomes, a number on par with protein-coding genes. Numerous studies have demonstrated that lncRNAs can influence gene expression programs but lack the temporal resolution to identify the immediate regulatory events. Thus, even for the most well-studied lncRNAs, the early and primary targets remain elusive, even though they are a prerequisite to elucidating lncRNA mechanisms. Here we describe a multifaceted effort to determine the primary targets of a lncRNA and the underlying temporal dynamics. We combine several genetically defined loss- and gain-of-function, rescue, and inducible lncRNA models to resolve gene regulatory events temporally from 30 minutes to four days. Applying this approach, we find that in mouse ES cells, the lncRNA Firre regulates the expression of 29 high-confidence target genes. Firre-regulated gene expression is not mediated by epigenetic events nor the proximal binding of the Firre lncRNA to its target genes. Instead, Firre induces nascent transcription and increases chromatin accessibility within minutes, resulting in mature transcripts of the primary target genes about an hour later. Overall, this study suggests Firre functions as a rapid RNA-based transcriptional regulator from a distance.