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Enrichment of conserved synaptic activity-responsive element in neuronal genes predicts a coordinated response of MEF2, CREB and SRF
Entity
UAM. Departamento de Biología MolecularPublisher
Public Library of ScienceDate
2013-01-31Citation
10.1371/journal.pone.0053848
Plos One 8.1 (2013): e53848
ISSN
1932-6203 (online)DOI
10.1371/journal.pone.0053848Funded by
This work was funded by the Ministerio de Ciencia e Innovación (MICINN) grants (SAF2008-00211; PIE- 200820I166), and a grant from the Spanish Comunidad de Madrid CCG08-CSIC/SAL-3464Project
Comunidad de Madrid. CCG08-CSIC/SAL-3464/CHEMOTUMORSubjects
Binding Sites; Cyclic AMP Response Element-Binding Protein; Myogenic Regulatory Factors; Neurons; Nucleic Acid; Biología y Biomedicina / BiologíaRights
© 2013 Rodríguez-Tornos et al.Abstract
A unique synaptic activity-responsive element (SARE) sequence, composed of the consensus binding sites for SRF, MEF2 and CREB, is necessary for control of transcriptional upregulation of the Arc gene in response to synaptic activity. We hypothesize that this sequence is a broad mechanism that regulates gene expression in response to synaptic activation and during plasticity; and that analysis of SARE-containing genes could identify molecular mechanisms involved in brain disorders. To search for conserved SARE sequences in the mammalian genome, we used the SynoR in silico tool, and found the SARE cluster predominantly in the regulatory regions of genes expressed specifically in the nervous system; most were related to neural development and homeostatic maintenance. Two of these SARE sequences were tested in luciferase assays and proved to promote transcription in response to neuronal activation. Supporting the predictive capacity of our candidate list, up-regulation of several SARE containing genes in response to neuronal activity was validated using external data and also experimentally using primary cortical neurons and quantitative real time RT-PCR. The list of SARE-containing genes includes several linked to mental retardation and cognitive disorders, and is significantly enriched in genes that encode mRNA targeted by FMRP (fragile X mental retardation protein). Our study thus supports the idea that SARE sequences are relevant transcriptional regulatory elements that participate in plasticity. In addition, it offers a comprehensive view of how activity-responsive transcription factors coordinate their actions and increase the selectivity of their targets. Our data suggest that analysis of SARE-containing genes will reveal yet-undescribed pathways of synaptic plasticity and additional candidate genes disrupted in mental disease
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Google Scholar:Rodríguez-Tornos, Fernanda M.
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San Aniceto, Iñigo
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Cubelos Álvarez, Beatriz
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Nieto, Marta A.
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