COACTIVATOR · Regulation of gene expression by transcriptional coactivators
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2013-12-01 → 2017-11-30
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
Регулацията на генното изразяване се изучава чрез SAGA комплекса, който контролира как дрождите реагират на промени в хранителните вещества. Това помага да се разбере как клетките вземат решения за своето развитие и как се сглобяват протеините, управляващи генетичната информация.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Regulation of gene expression by transcriptional coactivators
How cells respond to external changes by regulating gene expression is a fundamental question in biology. Our first objective is to better understand how cells allow both coordination and versatility in gene expression. Gene regulation can occur at many distinct steps. One critical point of control is transcription, which is regulated by many chromatin modifiers and remodelers, including the SAGA co-activator complex. We showed that, in fission yeast, SAGA regulates gene expression in response to a change in nutrient levels, downstream of both the TORC1 and TORC2 signaling pathways. We then established that the Taf12 subunit of SAGA becomes transiently phosphorylated upon starvation. This event is controlled by the opposing activities of the PP2A phosphatase, which is activated by TORC1, and the Gad8AKT kinase, which is activated by TORC2. Importantly, Taf12 phosphorylation functions to buffer the commitment to differentiation early upon starvation. Overall, our work reveals that SAGA is a direct target of nutrient-sensing pathways and has uncovered a mechanism by which TORC1 and TORC2 converge to control gene expression and cell fate decisions. Our second objective is to address how chromatin regulatory complexes are assembled and whether their assembly can be modulated to control their activities, focusing on the highly conserved SAGA co-activator. Its largest subunit, Tra1, is required for recruiting SAGA to promoters. Tra1 is a member of the PIKK family of kinases, but lacks catalytic residues. Recent work has established that PIKKs are activated by a novel chaperone, TTT. We accumulated biochemical and functional evidence that Tra1, although a pseudo-kinase, is assembled into SAGA by TTT. We identified key residues within SAGA and Tra1 that mediate their interaction and the domain of Tra1 which is recognized by TTT for its folding. Interestingly, this domain is conserved between all PIKKs, suggesting a shared molecular mechanism of assembly. Finally, we showed that TTT recognizes nascent, unfolded PIKKs, to catalyze their folding and incorporation into active complexes. In conclusion, our work has uncovered a previously unknown mechanism for the regulation of transcription by signaling pathways and strengthen an emerging concept in the field of signal transduction and gene regulation, which is that specific chaperones control the assembly of multi-protein complexes to coordinate their activities.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
How a cell responds to developmental or environmental changes by altering gene expression is a fundamental question in biology. Onecritical level of regulation is transcription initiation, which is controlled by large multiprotein complexes, including coactivators. Many studieshave shown that coactivators have distinct activities that play crucial roles in transcription, and their perturbation can cause cancer orneurodegeneration. Little is known, however, about how these activities integrate external signals to control transcription. I haveestablished one such coactivator, the highly conserved SAGA complex, as an excellent model to address this question. First, I discoveredthat, in the fission yeast Schizosaccharomyces pombe, SAGA regulates the switch from proliferation to differentiation. SAGA uses distinctactivities to function either as a repressor or as an activator of differentiation genes, depending on the levels of extracellular nutrients.Second, I discovered that S. pombe provides a unique opportunity to study the function of the largest SAGA subunit, Tra1. Its mammalianhomolog, TRRAP, is a key regulator of early embryogenesis and oncogenesis. My overall objective is to address key issues in theregulation of gene expression by focusing on SAGA, using a combination of genetic, genomic, biochemical, and proteomic approaches.One goal of this proposal is to identify which nutrient-sensing signaling pathway causes SAGA to switch from a repressor to an activator atthe promoters of differentiation genes. A second objective is to address the role of Tra1 in coordinating the activity of kinases sensingvarious cellular stresses and the regulatory roles of transcriptional coactivators. Overall, these studies will illuminate previously unknownmechanisms for the control of transcription by signal transduction pathways in eukaryotes.
Оригинален текст от CORDIS (на английски).
Участници
- CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisКоординаторФранция
Връзки
Данни: CORDIS, © Европейски съюз