The Silent Information Regulator (SIR) complex is responsible for the formation of silent chromatin domains in Saccharomyces cerevisiae, and consists of the NAD-dependent histone deacetylase Sir2, and histone binding proteins Sir3 and Sir4. The current model of silent chromatin assembly proposes that histone deacetylation by Sir2 is required to promote recruitment of Sir3 and Sir4, and assembly of full SIR complexes on chromatin. However, recent work has suggested unique roles for the histone binding proteins Sir3 and Sir4 in this process. Here we present data suggesting that Sir3 is primarily responsible for mediating the spreading of silent chromatin from sites of nucleation, while regulation of Sir4 abundance controls the rate of silencing establishment. We have also investigated a potential novel dimerization domain in Sir3, which may represent a conserved function in vertebrates. Investigations into the regulation of silent chromatin assembly in budding yeast will facilitate our understanding of the mechanisms that control heterochromatin-mediated gene repression in higher organisms.

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La complexe protéique Sir (Silent Information Regulator) de la levure bourgeonnante est l’acteur principal dans la formation de l’hétérochromatine, qui provoque l’atténuation de l’expression génique par un mécanisme épigénétique. Le complexe Sir lié à la chromatine maternelle est démonté lors de la réplication génomique et puis réformé sur les deux brins nouvellement répliqué. La dynamique de maintien de Sir sur la chromatine pendant le cycle cellulaire et dans de variables conditions de croissance n’est pas bien comprise. Pour comprendre comment la structure chromatinienne telle que l’hétérochromatine peut être héritée et par conséquent comment les structures épigénétiques sont transmises d’une génération cellulaire à l’autre, nous avons besoin de mesurer la vitesse d’échange des sous-unités du complexe Sir au cours du cycle cellulaire dans différentes conditions de croissance. Nous avons donc utilisé le système RITE qui permet d’échanger deux épitopes attachés à Sir3 (une des sous-unités de Sir) et par la suite mesurer la cinétique de remplacement de Sir3. Nous avons constaté que la Sir3 maternelle est complètement remplacée par la Sir3 nouvellement synthétisées dans les régions télomériques durant le premier cycle cellulaire après la sortie de la phase stationnaire. Nous proposons que cette reprogrammation du complexe hétérochromatique est un mécanisme d’adaptation qui assure l’activation des gènes de réponse au stress par la déstabilisation transitoire de la structure hétérochromatinienne. / The budding yeast SIR complex (Silent Information Regulator) is the principal actor in heterochromatin formation, which causes epigenetically regulated gene silencing phenotypes. The maternal chromatin bound SIR complex is disassembled during replication and then, if heterochromatin is to be restored on both daughter strands, the SIR complex has to be reformed on both strands to pre-replication levels. The dynamics of SIR complex maintenance and re-formation during the cell-cycle and in different growth conditions are however not clear. Understanding exchange rates of SIR subunits during the cell cycle and their distribution pattern to daughter chromatids after replication has important implications for how heterochromatic states may be inherited and therefore how epigenetic states are maintained from one cellular generation to the next. We therefore used the tag switch RITE system to measure genome wide turnover rates of the SIR subunit Sir3 before and after exit from stationary phase and show that maternal Sir3 subunits are completely replaced with newly synthesized Sir3 at subtelomeric regions during the first cell cycle after release from stationary phase. We propose that the observed “reset” of the heterochromatic complex is an adaptive mechanism that ensures the activation of subtelomeric stress response genes by transiently destabilizing heterochromatin structure.

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Errata pasted into front. Bibliography: leaves 425-440. This thesis aims to assess the impact of late nineteenth/early twentieth century science (especially neurology, psychology and physics) on Mitchell's philosophical work and trends in philosophical psychology during that period. It also aims to demonstrate the importance of Mitchell's philosophical work in the context of contemporary theories of mind and content, cognitive science and the philosophy of science and perception, to make clear the extent of Mitchell's philosophical influence on others at the time and to locate Mitchell's work in relation to other influences on philosophy in Australia.

Errata pasted into front. / Bibliography: leaves 425-440. / xii, 445 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis aims to assess the impact of late nineteenth/early twentieth century science (especially neurology, psychology and physics) on Mitchell's philosophical work and trends in philosophical psychology during that period. It also aims to demonstrate the importance of Mitchell's philosophical work in the context of contemporary theories of mind and content, cognitive science and the philosophy of science and perception, to make clear the extent of Mitchell's philosophical influence on others at the time and to locate Mitchell's work in relation to other influences on philosophy in Australia. / Thesis (Ph.D.)--University of Adelaide, Dept. of Philosophy, 2001?

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