The long noncoding RNA FOSIL shapes the dynamics of FOS induction

Abstract

Immediate-early genes require rapid, transient, and precisely tuned transcriptional activation in response to extracellular signals, yet how this kinetic precision is achieved remains poorly understood. We characterize FOSIL (LINC01220), an inducible lncRNA locus downstream of FOS. Depleting FOSIL RNA delays heregulin (HRG)-induced FOS mRNA and protein accumulation and prolongs the response, indicating that FOSIL sharpens both the onset and the shutoff of the induction wave. Capture Micro-C maps show that FOSIL depletion weakens the chromatin boundary between FOS and FOSIL and increases local compaction across the pre-assembled FOS-FOSIL neighborhood during serum starvation, demonstrating that basal FOSIL production maintains a locally insulated, poised conformation prior to signal arrival. Upon HRG stimulation, FOSIL depletion blunts the rapid movement of the locus toward nuclear speckles, diminishes early speckle-proximal FOS transcription, and extends late firing at speckle-distant alleles. At single transcription active sites, nascent FOSIL activity correlates with closer speckle proximity and higher FOS output, and activating the endogenous FOSIL promoter by CRISPRa, but not supplying FOSIL RNA in trans, enhances both speckle association and FOS induction. Together, these findings support a mechanism where endogenous FOSIL activity coordinates pre-stimulus chromatin folding with dynamic nuclear speckle positioning to fine-tune the onset, amplitude, and resolution of immediate-early gene expression.