Regulation of neural gene transcription by optogenetic inhibition of the RE1-silencing transcription factor.

Proc Natl Acad Sci U S A 2016 Jan 23;113(1):E91-100. Epub 2015 Dec 23.

Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, 16132 Genova, Italy; Department of Experimental Medicine, University of Genova, 16132 Genova, Italy

Optogenetics provides new ways to activate gene transcription; however, no attempts have been made as yet to modulate mammalian transcription factors. We report the light-mediated regulation of the repressor element 1 (RE1)-silencing transcription factor (REST), a master regulator of neural genes. To tune REST activity, we selected two protein domains that impair REST-DNA binding or recruitment of the cofactor mSin3a. Computational modeling guided the fusion of the inhibitory domains to the light-sensitive Avena sativa light-oxygen-voltage-sensing (LOV) 2-phototrophin 1 (AsLOV2). By expressing AsLOV2 chimeras in Neuro2a cells, we achieved light-dependent modulation of REST target genes that was associated with an improved neural differentiation. In primary neurons, light-mediated REST inhibition increased Na(+)-channel 1.2 and brain-derived neurotrophic factor transcription and boosted Na(+) currents and neuronal firing. This optogenetic approach allows the coordinated expression of a cluster of genes impinging on neuronal activity, providing a tool for studying neuronal physiology and correcting gene expression changes taking place in brain diseases.

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http://dx.doi.org/10.1073/pnas.1507355112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711829PMC
January 2016
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