Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS

Periodic Report Summary 1 - COACTIVATOR (Regulation of gene expression by transcriptional coactivators)

How a cell responds to external changes by regulating gene expression is a fundamental question in biology. The coordinated balance between proliferation and differentiation is crucial for all organisms and is altered in many diseases. Our overall objective is to address how gene expression is regulated in response to nutrient availability to control cell fate decisions. Using the fission yeast S. pombe as a model system, we and others established that the TOR kinase-containing complexes, TORC1 and TORC2, and the SAGA transcriptional co-activator complex control the expression of differentiation genes in response to nutrient availability.
Our first aim is to address how SAGA is regulated by the TOR signaling pathways. We have indeed discovered that, depending on nutrient levels, SAGA is controlled by either TORC1 or TORC2 to regulate the expression of differentiation genes. Strikingly, we found that the TORC1 and TORC2 pathways oppose each other in the phosphorylation of the SAGA subunit Taf12, in response to nutrient availability. We are now investigating how Taf12 phosphorylation affects SAGA regulatory activities at the promoters of differentiation genes. Overall, we expect to uncover a novel mechanism by which the TOR kinase regulates gene expression and establish that transcriptional co-activators can be directly controlled by signaling pathways.
In parallel, we are investigating the roles of the ASTRA complex in the regulated assembly of the TOR and SAGA complexes in response to nutrient availability and the control of cell fate decisions. ASTRA is a highly conserved HSP90 co-chaperone required for the assembly of the TORC1 and TORC2 complexes. Our second aim is to test the hypothesis that ASTRA plays a central role in nutrient sensing, by allowing cells to switch from using TORC1, in rich conditions, to TORC2 upon starvation. Specifically, we expect to decipher the molecular mechanism by which nutrient availability controls ASTRA co-chaperone activity towards the TOR complexes.
Finally, our third aim is based on our recent observation that the ASTRA co-chaperone interacts with one SAGA subunit, Tra1/TRRAP. We are thus addressing whether ASTRA also functions at chromatin, to incorporate Tra1 into the SAGA complex at the promoters of differentiation genes. This work would establish that SAGA recruitment and activation are tightly controlled by chaperone-dependent complex assembly. Furthermore, we are addressing whether similar mechanisms control the balance between proliferation and differentiation of cancer stem cells.
Overall, our model is that the TOR pathways control SAGA in response to nutrient availability. ASTRA would reinforce this regulation by coordinating the activities of the TOR kinase-containing complexes, in the cytoplasm, with the functions of Tra1 and of the SAGA complex, at specific promoters. To test this model, we will combine classical genetics and biochemistry with quantitative proteomic and high-throughput genomic approaches.
In conclusion, our studies have the potential to illuminate previously unknown mechanisms for the control of transcription by signal transduction pathways. Additionally, our findings would strengthen an emerging concept in the field of signal transduction and gene expression regulation, which is that specific chaperones control the assembly of multi-protein complexes to coordinate their activities.

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