Rapid transcription of arc/arg3.1 and other very fast immediate early genes in response to neuronal activity is mediated by a stalled RNA polymerase II mechanism

Transcription of immediate early genes (IEGs) in neurons is exquisitely sensitive to neuronal activity, but the mechanism underlying the earliest of these transcription events is largely unknown. Here we demonstrate that very fast IEGs (VF-IEGs) such as arc/arg3.1 are poised for rapid transcription by the stalling of RNA Polymerase II (Pol II) just downstream of the transcription start site. RNAi-depletion of two subunits of Negative Elongation Factor, a mediator of Pol II stalling, reduces the Pol II occupancy of the arc promoter and compromises the rapid induction of arc and other VF-IEGs. In contrast, reduction of Pol II stalling did not prevent expression of fast IEGs (F-IEGs). These F-IEGs are expressed with comparatively slower kinetics and largely lack promoter proximal Pol II stalling. Taken together, our data strongly indicate that very fast kinetics of neuronal IEG expression require poised Pol II and suggest a role for this mechanism in transcription-dependent learning and memory. Overall design: Examination of Pol II bindnig genome-wide in rat neurons