title: Stimulus-specific combinatorial functionality of neuronal c-fos enhancers.
abstract: The c-fos gene (also known as Fos) is induced by a broad range of stimuli and is a reliable marker for neural activity. Its induction mechanism and available reporter mouse lines are based exclusively on c-fos promoter 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.
authors.affiliation: Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jae-Yeol
authors.initials: JY
authors.lastname: Joo
authors.affiliation: Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Schaukowitch
authors.affiliation: Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Lukas
authors.initials: L
authors.lastname: Farbiak
authors.affiliation: Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Gokhul
authors.initials: G
authors.lastname: Kilaru
authors.affiliation: Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Tae-Kyung
authors.initials: TK
authors.lastname: Kim
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004622:Embryo, Mammalian; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D015870:Gene Expression; D016762:Genes, fos / Q000502:physiology*; D051379:Mice; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D014158:Transcription, Genetic
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger