Dissecting the (epi)genetic origins of phenotypic variation and metabolic disease susceptibility

Informations projet

DismantlingNoise

N° de convention de subvention: 682679

DOI

10.3030/682679

Projet clôturé le 30 Novembre 2018

Date de signature de la CE 28 Septembre 2016

Date de début 1 Janvier 2017

Date de fin 31 Decembre 2021

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 997 853,00

Contribution de l’UE

€ 1 997 853,00

Coordonné par

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 2 - DismantlingNoise (Dissecting the (epi)genetic origins of phenotypic variation and metabolic disease susceptibility)

Période du rapport: 2018-07-01 au 2019-12-31

Résumé du contexte et des objectifs généraux du projet

In this project, I proposed three aims dedicated towards understanding how different each one of us could have been. Our focus was the metabolic disease context but its relevance extends far beyond that. The prevalence of obesity is predicted to be 1 billion by the year 2030. As a critical risk factor for heart disease, diabetes and stroke, obesity represents one of the chief socio-economic challenges of our day. While we understand the genetic underpinnings of obesity with increasing robustness, important regulatory layers, and in particular non-genetic regulation, remain poorly understood. A perfect example, we know that genetically identical mice can vary by as much as 100% in body weight when fed a high fat diet; currently, we have no mechanistic explanation for the emergence of such phenotypic variation. Our first goal was to catalogue epigenome and phenome variation to an unprecedented depth and resolution in the isogenic context. We aimed also to examine two completely novel models of epigenetically sensitized obesity and thus begin a mechanistic dissection of this phenotypic variation. And finally, we began mapping a series of gene-gene and gene-environment epistasis interactions including eight models of developmental plasticity and approximately a dozen chromatin regulator mutants. The latter epistasis matrix was geared to help identify the molecular mechanisms that trigger, amplify and buffer phenotypic variation and stochastic obesity in mice and will continue through other funding channels in the future.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

As indicated above, our first goal was to catalogue epigenome and phenome variation to an unprecedented depth and resolution. Because of the premature termination of the grant, this goal, which was to rely heavily upon a 3rd party sub-contract with the German and French mouse clinics was never initiated. Pilot studies did however reveal the value of such an effort in the future through the identification of reproducible subclusters of epigenetically variable animals. We also aimed to examine two completely novel models of epigenetically sensitized bi-stable obesity and thus begin a mechanistic dissection of phenotypic variation. One of these lead to the discovery of a brand new murine/mammalian polyphenism where the atypical morph displays a stark gigantism, attaining lean mass ~ 15% larger than normal, and approximately 25% additional fat mass. Similar findings we believe may contribute substantially to the current epidemic of obesity and related metabolic disease, particularly in children. Finally, we began mapping a series of gene-gene and gene-environment epistasis interactions including eight models of developmental plasticity and approximately a dozen chromatin regulator mutants. These efforts lead to the identification of strong parental and genetic dependencies and establish a framework for future focused genetic dissection of variation. Again because of the highly premature termination of the grant the latter two goals were truncated and there was insufficient data or time to disseminate the preliminary data obtained thus far. These projects will ultimately continue, albeit delayed for lack of dedicated funding.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

N/A. The project was prematurely terminated at a stage where all data were still preliminary.