title: Enrichment of conserved synaptic activity-responsive element in neuronal genes predicts a coordinated response of MEF2, CREB and SRF.
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.
authors: Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, Campus de Cantoblanco, Madrid, Spain.
authors: Fernanda M
authors: FM
authors: Rodríguez-Tornos
authors: Iñigo
authors: I
authors: San Aniceto
authors: Beatriz
authors: B
authors: Cubelos
authors: Marta
authors: M
authors: Nieto
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D026161:MADS Domain Proteins / Q000235:genetics* / Q000378:metabolism; D064326:MEF2 Transcription Factors; D051379:Mice; D046912:Multiprotein Complexes; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D026362:Serum Response Factor / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D046912:Multiprotein Complexes; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; D026362:Serum Response Factor; C115163:CREB1 protein, human; C578035:MEF2A protein, human; C476858:SRF protein, human; C092069:activity regulated cytoskeletal-associated protein
references: Neurosci Lett. 2006 Nov 27;409(1):10-3
references: 17034946
references: Nat Neurosci. 2009 Oct;12(10):1238-47
references: 19657336
references: Genome Res. 2012 Apr;22(4):611-22
references: 22300767
references: Science. 2006 Feb 17;311(5763):1008-12
references: 16484497
references: J Neurosci. 2002 Dec 1;22(23):10067-71
references: 12451105
references: Neurochem Int. 2011 Nov;59(6):787-803
references: 21884744
references: Trends Biochem Sci. 2008 Apr;33(4):161-70
references: 18374575
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D832-6
references: 19015121
references: Cell Calcium. 2007 Oct-Nov;42(4-5):363-71
references: 17618683
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W403-7
references: 15980499
references: J Neurosci. 2005 May 4;25(18):4587-92
references: 15872106
references: Nat Neurosci. 2006 Feb;9(2):163-6
references: 16439983
references: Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):316-21
references: 19116276
references: Cell. 2003 Sep 5;114(5):545-57
references: 13678579
references: Cell. 2003 Sep 19;114(6):777-89
references: 14505576
references: Cell. 2008 Oct 31;135(3):396-400
references: 18984148
references: J Neurosci. 2002 Jan 1;22(1):167-75
references: 11756499
references: Am J Psychiatry. 2006 Sep;163(9):1622-9
references: 16946189
references: Neuron. 2010 May 27;66(4):523-35
references: 20510857
references: Trends Neurosci. 2010 May;33(5):230-40
references: 20223527
references: Am J Hum Genet. 2005 Jun;76(6):1074-80
references: 15877281
references: Neuron. 1999 Jul;23(3):583-92
references: 10433269
references: Nat Genet. 2011 Jun;43(6):585-9
references: 21572417
references: Neuron. 2009 Aug 27;63(4):466-81
references: 19709629
references: Hum Mol Genet. 2011 Sep 1;20(17):3366-75
references: 21624971
references: Science. 2001 Nov 2;294(5544):1030-8
references: 11691980
references: Curr Opin Neurobiol. 2009 Jun;19(3):263-74
references: 19541473
references: Mol Brain. 2009 Mar 05;2:7
references: 19265511
references: Trends Neurosci. 2010 Feb;33(2):67-75
references: 19963289
references: Cell. 2011 Jul 22;146(2):247-61
references: 21784246
references: Nat Neurosci. 2005 Jun;8(6):759-67
references: 15880109
references: J Neurosci. 2011 Dec 14;31(50):18237-50
references: 22171029
references: Nature. 2010 May 13;465(7295):182-7
references: 20393465
references: Nature. 2008 Oct 30;455(7217):1198-204
references: 18815592
references: Neuron. 2010 Feb 25;65(4):445-59
references: 20188650
references: Cell. 2008 Oct 31;135(3):401-6
references: 18984149