Assuntos
Envelhecimento/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Fatores Etários , Envelhecimento/genética , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead , Genótipo , Longevidade , Modelos Animais , Fenótipo , Transdução de Sinais , Transativadores/genética , Fatores de Transcrição/genéticaRESUMO
Reduced insulin/IGF-1-like signaling (IIS) extends C. elegans lifespan by upregulating stress response (class I) and downregulating other (class II) genes through a mechanism that depends on the conserved transcription factor DAF-16/FOXO. By integrating genome-wide mRNA expression responsiveness to DAF-16 with genome-wide in vivo binding data for a compendium of transcription factors, we discovered that PQM-1 is the elusive transcriptional activator that directly controls development (class II) genes by binding to the DAF-16-associated element (DAE). DAF-16 directly regulates class I genes only, through the DAF-16-binding element (DBE). Loss of PQM-1 suppresses daf-2 longevity and further slows development. Surprisingly, the nuclear localization of PQM-1 and DAF-16 is controlled by IIS in opposite ways and was also found to be mutually antagonistic. We observe progressive loss of nuclear PQM-1 with age, explaining declining expression of PQM-1 targets. Together, our data suggest an elegant mechanism for balancing stress response and development.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Longevidade , Transativadores/metabolismo , Animais , Fatores de Transcrição Forkhead , Receptor de Insulina/metabolismo , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/metabolismo , Ativação TranscricionalRESUMO
Accurate and comprehensive information about the nucleotide sequence specificity of trans-acting factors (TFs) is essential for computational and experimental analyses of gene regulatory networks. We present the Yeast Transfactome Database, a repository of sequence specificity models and condition-specific regulatory activities for a large number of DNA- and RNA-binding proteins in Saccharomyces cerevisiae. The sequence specificities in TransfactomeDB, represented as position-specific affinity matrices (PSAMs), are directly estimated from genomewide measurements of TF-binding using our previously published MatrixREDUCE algorithm, which is based on a biophysical model. For each mRNA expression profile in the NCBI Gene Expression Omnibus, we used sequence-based regression analysis to estimate the post-translational regulatory activity of each TF for which a PSAM is available. The trans-factor activity profiles across multiple experiments available in TransfactomeDB allow the user to explore potential regulatory roles of hundreds of TFs in any of thousands of microarray experiments. Our resource is freely available at http://bussemakerlab.org/TransfactomeDB/
