FIGURE 1. Mechanisms of neuronal activity-induced transcription.

The diagrams represent four steps in the process of Fos transcription that are regulated by neural activity. a) Prior to neuronal activity, the Fos promoter is primed for response by the association of sequence-specific DNA binding transcription factors with stimulus-response elements (gray boxes) in the proximal promoter. RNA polymerase II (Pol II) is also pre-associated with the Fos promoter prior to activation. Numbers show base pair distances of each element from the transcription start site (TSS). The promoter is kept off in part by the local recruitment of HDACs. Key sites of calcium-regulated phosphorylation are represented by the circled letter P. b) Calcium induces a switch in cofactors present at the Fos promoter, with recruitment of the co-activator and histone acetyltransferase CBP and loss of the repressive HDACs. c) Distal enhancer elements (E.E.) contribute to activity-dependent transcription. These elements are bound by transcription factors including SRF and CREB, and show calcium-dependent recruitment of CBP and Pol II binding. Chromatin looping may bring the enhancer into physical proximity of the proximal promoter and Fos TSS. d) Transcription elongation is regulated by stimulus-dependent phosphorylation of two sites in the C-terminal domain of the large subunit of RNA polymerase II. The pre-initiation form of RNA Pol II is bound to the Fos promoter but is not competent to drive RNA synthesis. Phosphorylation of serine 5 (pSer5) is sufficient to promote engagement but results in polymerase stalling within the transcribed region of many genes. Productive elongation requires additional phosphorylation of RNA Pol II at serine 2 (pSer2).