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

Informazioni relative al progetto

DismantlingNoise

ID dell’accordo di sovvenzione: 682679

DOI

10.3030/682679

Progetto concluso il 30 Novembre 2018

Data della firma CE 28 Settembre 2016

Data di avvio 1 Gennaio 2017

Data di completamento 31 Dicembre 2021

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 1 997 853,00

Contributo UE

€ 1 997 853,00

Coordinato da

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)

Periodo di rendicontazione: 2018-07-01 al 2019-12-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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