DREAM controls the on/off switch of specific activity-dependent transcription pathways

Mellström, Britt; Sahún, Ignasi; Ruiz Nuño, Ana; Murtra, Patricia; Gómez Villafuertes, Rosa; Savignac, Magalí; Oliveros, Juan C.; González, Paz; Kastanauskaite, Asta; Knafo, Shira; Zhuo, Min; Higuera Matas, Alejandro; Errington, Michael L.; Maldonado, Rafael, 1961-; De Felipe, Javier; Jefferys, John G.R.; Bliss, Tim V. P.; Dierssen, Mara; Naranjo, José R.

doi:http://dx.doi.org/10.1128/MCB.00360-13

DREAM controls the on/off switch of specific activity-dependent transcription pathways

Citation

Mellström B, Sahún I, Ruiz-Nuño A, Murtra P, Gomez-Villafuertes R, Savignac M et al. DREAM controls the on/off switch of specific activity-dependent transcription pathways. Mol Cell Biol. 2014 Mar;34(5):877-87. DOI: 10.1128/MCB.00360-13

Abstract

Changes in nuclear Ca(2+) homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K(+) channel interacting protein 3), is a Ca(2+)-binding protein that binds DNA and represses transcription in a Ca(2+)-dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca(2+)-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Using genome-wide analysis, we show that DREAM regulates the expression of specific activity-dependent transcription factors in the hippocampus, including Npas4, Nr4a1, Mef2c, JunB, and c-Fos. Furthermore, DREAM regulates its own expression, establishing an autoinhibitory feedback loop to terminate activity-dependent transcription. Ablation of DREAM does not modify activity-dependent transcription because of gene compensation by the other KChIP family members. The expression of daDREAM in the forebrain resulted in a complex phenotype characterized by loss of recurrent inhibition and enhanced long-term potentiation (LTP) in the dentate gyrus and impaired learning and memory. Our results indicate that DREAM is a major master switch transcription factor that regulates the on/off status of specific activity-dependent gene expression programs that control synaptic plasticity, learning, and memory.