The lncRNA Firre functions as a transcriptional activator from a distance

Numerous studies have now demonstrated that lncRNAs can influence gene expression programs leading to cell and organismal phenotypes. Typically, lncRNA perturbations and concomitant changes in gene expression are measured on the timescale of many hours to days. Thus, we currently lack a temporally grounded understanding of the primary, secondary, and tertiary relationships of lncRNA-mediated transcriptional and epigenetic regulation - despite being a prerequisite to elucidating lncRNA mechanisms. To begin to address when and where a lncRNA regulates gene expression, we genetically engineered cell lines to temporally induce the lncRNA Firre. Using this approach, we were able to monitor lncRNA transcriptional regulatory events from 15 min to four days. We observed that upon induction, Firre RNA regulates epigenetic and transcriptional states, in trans, within 30 min. These early regulatory events result in much larger transcriptional changes after twelve hours, well before current studies monitor lncRNA regulation. Moreover, Firre-mediated gene expression changes are epigenetically remembered for days. Overall, this study suggests that lncRNAs can rapidly regulate gene expression by establishing persistent epigenetic and transcriptional states.