EPOC · Understanding the molecular basis of stochastic bi-stable obesity
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-12-01 → 2018-11-30
- EU contribution
- €159,461
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Understanding the molecular basis of stochastic bi-stable obesity
Recent estimates place obesity incidence at more than 600 millions of people worldwide. The long-term implications of this disease include exacerbation of global heart disease, diabetes, and cancer, making obesity one of the world's chief socio-economic challenges of the next decade. People are not all equal when it comes to emergence of obesity. Indeed, some populations seem protected, others seem prone to its development. Population level phenotypic variation, which describes the variability of a phenotype in a given population, is thought to serve as a mechanistic platform for adaptation and evolution. Phenotypic variation can be of genetic and/or epigenetic origin. Whereas, the last decade has seen much progress in obesity genetics, our understanding of epigenetic regulation of the disease is poor. Our lab recently published data about specific mutant mice developing an unprecedented bi-stable stochastic obesity phenotype. Approximately 20% of the genetically identical, littermate-controlled heterozygous mutant mice develop obesity while the remaining ~80% remain as lean as wild-type littermates, resulting in a bi-modal body weight distribution in the population. Here, we proposed to map the molecular basis of a chromatin state dependent epigenetic switch that to the best of our knowledge buffers metabolic programming, establishes phenotypic bi-stability and thereby generate a deeper understanding of the mechanisms underlying bi-stable obesity.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENCoordinatorGermany
Links
Data: CORDIS, © European Union