Stimulus-specific combinatorial functionality of neuronal c-fos enhancers

The c-fos gene is induced by a broad range of stimuli and is commonly used as a reliable marker for neural activity. The authors demonstrate that the combinatorial activation of multiple enhancers surrounding the c-fos gene is a critical mechanism of ensuring robust c-fos gene induction in response to various stimuli. The c-fos gene (also known as Fos ) is induced by a broad range of stimuli and is a reliable marker for neural activity. Here we demonstrate that multiple enhancers surrounding the c-fos gene are crucial for ensuring robust c-fos response to various stimuli. Membrane depolarization, brain-derived neurotrophic factor (BDNF) and forskolin activate distinct subsets of the enhancers to induce c-fos transcription in neurons, suggesting that stimulus-specific combinatorial activation of multiple enhancers underlies the broad inducibility of the c-fos gene. Accordingly, the functional requirement of key transcription factors varies depending on the type of stimulation. Combinatorial enhancer activation also occurs in the brain. Providing a comprehensive picture of the c-fos induction mechanism beyond the minimal promoter, our study should help in understanding the physiological nature of c-fos induction in relation to neural activity and plasticity.