Objective 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. Fields of science medical and health sciencesclinical medicineendocrinologydiabetesnatural scienceschemical sciencesanalytical chemistrycalorimetrymedical and health sciencesclinical medicineoncologymedical and health scienceshealth sciencesnutritionobesitynatural sciencesbiological sciencesgeneticsepigenetics Programme(s) 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 Topic(s) MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Call for proposal H2020-MSCA-IF-2015 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Net EU contribution € 159 460,80 Address HOFGARTENSTRASSE 8 80539 Munchen Germany See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 159 460,80