Obiettivo The spatial organisation of the genome in the nucleus has a role in the regulation of gene expression. In vertebrates, chromosomal regions with low gene-density, and that are less transcribed, are located close to the nuclear periphery. Correlations have also been made between the transcriptional state of some genes and their location near the nuclear periphery. For example, the proneural Mash1 gene relocates away from the nuclear periphery when it is activated during neural differentiation of mouse embryonic stem (ES) cells. Recently, the host laboratory demonstrated that the nuclear periphery plays a direct role in gene repression by experimentally relocating genomic loci to the nuclear envelope. A crucial issue is whether this nuclear reorganisation is important for correct differentiation and development. To do this I will impair the relocation of Mash1 in ES cells by tethering it to the nuclear envelope with the lacO/lacI-lap2b system set up in the host laboratory. The consequences of this anchoring on Mash1 transcription and neural cell differentiation will be assessed. I also propose to investigate the mechanism of Mash1 relocation. First I will determine whether the nuclear position of Mash1 influences its chromatin state, by establishing the histone modifications of the locus, when tethered or not. Then I will address whether nuclear reorganisation is an active or passive process. In live cells, I will track the position of the lacO tagged Mash1 visualized with lacI fused to GFP, during neural differentiation. Finally, I will determine the endogenous pathways that retain specific loci at the nuclear periphery. I will perform two high-throughput screens on a human cell line established in the lab where a peripheral locus is visualized by laco/lacI-GFP. An siRNA screen and a small molecule screen will be used to look for factors whose loss or inhibition lead to displacement of the lacO-tagged locus away from the nuclear edge. Campo scientifico natural sciencesbiological sciencesgeneticsgenomes Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2009-IEF - Marie Curie Action: "Intra-European Fellowships for Career Development" Invito a presentare proposte FP7-PEOPLE-2009-IEF Vedi altri progetti per questo bando Meccanismo di finanziamento MC-IEF - Intra-European Fellowships (IEF) Coordinatore THE UNIVERSITY OF EDINBURGH Contributo UE € 180 103,20 Indirizzo OLD COLLEGE, SOUTH BRIDGE EH8 9YL Edinburgh Regno Unito Mostra sulla mappa Regione Scotland Eastern Scotland Edinburgh Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Angela Noble (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato Partecipanti (1) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto MEDICAL RESEARCH COUNCIL Partecipazione conclusa Regno Unito Contributo UE Nessun dato Indirizzo 20 Park Crescent W1B 1AL LONDON Mostra sulla mappa Tipo di attività Public bodies (excluding Research Organisations and Secondary or Higher Education Establishments) Contatto amministrativo Wendy Bickmore (Prof.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato
