Obiettivo Substantial evidence indicates that even when genetically matched, we are not created equal. The mechanisms underlying such non-Mendelian phenotype variation are sufficient to elicit complex disease but remain unknown. In this context, the regulators of chromatin state have the ability to establish cellular memory, which is encoding specific silenced gene expression states through mitosis and is involved in control phenotypic variation.Interestingly, two chromatin ‘stabilizing’ genes (Trim28 / Dnmt3a) and two obesity buffering ‘effector’ genes (Peg3 / Nnat) are involved in triggering bi-stable epigenetic obesity. This present proposal aims at intersecting all four models of polyphenism to identify the core transcriptional and chromatin machinery required to establish and switch ‘On’ or ‘Off’ the Obese state. Thus, I will to explore these four mutants [Trim28(D9/+), Dnmt3a(+/-), Peg3(+/-p), and Nnat(+/-p)], which will serve as a biological filter to reveal core requirements.First, I will define co-variation of a spectrum of complex trait phenotypes resulting from insufficiency at each of these loci. Then, I will decipher the mechanism underlying their sensitized bi-stable obesity. Third, I will assess the epigenetic basis of their buffering of polyphenism.The aim of this proposal is to precisely provide, for the first time, reference-depth phenomic and epigenomic profiling of chromatin sensitizer- (Trim28- / Dnmt3a-) and chromatin effector- (Peg3- / Nnat-) induced stochastic obesity. The work will uncover the first definitive genetic and genomic templates for probing non-Mendelian phenotypic variation and stochastic obesity and thus highlight new therapeutic perspectives. Campo scientifico medical and health sciencesclinical medicineendocrinologydiabetesnatural scienceschemical sciencesanalytical chemistrycalorimetrymedical and health sciencesclinical medicineoncologymedical and health scienceshealth sciencesnutritionobesitynatural sciencesbiological sciencesgeneticsepigenetics Programma(i) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Argomento(i) MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Invito a presentare proposte H2020-MSCA-IF-2015 Vedi altri progetti per questo bando Meccanismo di finanziamento MSCA-IF-EF-ST - Standard EF Coordinatore MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Contribution nette de l'UE € 159 460,80 Indirizzo HOFGARTENSTRASSE 8 80539 Munchen Germania Mostra sulla mappa Regione Bayern Oberbayern München, Kreisfreie Stadt Tipo di attività Research Organisations Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 159 460,80