Regulation of neural gene transcription by optogenetic inhibition of the RE1-silencing transcription factor
| Autor: | Federico Pecoraro Bisogni, Helena Scarongella, Stefania Criscuolo, Emanuele Carminati, Fabio Benfenati, Fabrizia Cesca, Luca Maragliano, Francesco Paonessa, Davide Amoroso, Silvio Sacchetti, Giacomo Pruzzo |
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| Přispěvatelé: | Paonessa, FRANCESCO GIUSEPPE, Criscuolo, Stefania, Sacchetti, Silvio, Amoroso, Davide, Scarongella, Helena, Bisogni, Federico Pecoraro, Carminati, Emanuele, Pruzzo, Giacomo, Maragliano, Luca, Cesca, Fabrizia, Benfenati, Fabio |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
AsLOV2 Avena Transcription Genetic Response element Electrophoretic Mobility Shift Assay RE1-silencing transcription factor REST/NRSF Mice Transduction Genetic Plant Proteins Genetics Regulation of gene expression Neurons Tumor Multidisciplinary biology General transcription factor Plant Protein food and beverages Chromatin Cell biology Dynamics PNAS Plus Transcription Protein Binding Protein Structure Recombinant Fusion Proteins Dynamic E-box Cell Line 03 medical and health sciences Transduction Sp3 transcription factor Genetic Cell Line Tumor Animals Transcription factor ATF3 Animal Molecular DNA Neuron Repressor Protein Protein Structure Tertiary Optogenetics Repressor Proteins 030104 developmental biology Gene transcription Gene Expression Regulation biology.protein Tertiary Optogenetic Recombinant Fusion Protein |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 113(1) |
| ISSN: | 1091-6490 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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