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Research Interest:

Despite a strong genetic contribution to obesity and diabetes, genome wide association studies have identi?ed variants that can only explain less than 10% of the observed heritability. This discrepancy, known as the missing heritability problem, has stimulated research aimed at understanding the bases and possible explanations for this observation. One prominent hypothesis, now supported by substantial amount of experimental evidence, points at epigenetic inheritance. Parental environmental experiences indeed cause phenotypic variation in unexposed offspring through genetic-independent epigenetic mechanisms. Beside environmentally acquired epigenetic inheritance, published ?ndings and our own preliminary data suggest that parental genetics can also control phenotypic variation in the wild-type progeny through epigenetic mechanisms.

Project Title:

Parental control of offspring health: characterisation of novel genetic determinants of (epi)genetic inheritance and phenotypic variation in mammals

Project Description:

A preliminary in silico screening in our lab, using data from the International Mouse Phenotyping Consortium (IMPC), identified several potential non-canonical epigenetic modifiers. Aim of this PhD project is to further characterise one of these candidates, by reproducing the phenotype in a more controlled environment and taking into account maternal and paternal contributions; and by identifying the molecular mechanisms by which parental genetics affects offspring phenotypic trajectories. In particular, the PhD student will generate cohorts of wild-type animals coming from either mutant parents or isogenic control individuals and run an in-depth metabolic phenotyping, which includes monitoring of body weight and composition, glucose tolerance, insulin sensitivity, energy expenditure and response to dietary challenges. For the mechanistic dissection of the parental effects, the PhD candidate will discriminate germ-cell dependent and independent mechanisms by applying state-of-the art bulk and single cell molecular profilings such as RNA-, Chip- and ATAC-Seq.

The overall goal of the project will be to identify and mechanistically characterise novel genetic determinants of (epi)genetic inheritance of metabolic phenotypes in mammals.

 

Selected Publications:

Gerlini R, Berti L, Darr J, Lassi M, Brandmaier S, Fritsche L, Scheid F, Böhm A, Königsrainer A, Grallert H, Häring HU, Hrabe de Angelis M, Staiger H, Teperino R. Glucose tolerance and insulin sensitivity de?ne adipocyte transcriptional programs in human obesity. Mol Metab. 2018 Dec;18:42-50. doi:10.1016/j.molmet.2018.09.004.

Lu TT, Heyne S, Dror E, Casas E, Leonhardt L, Boenke T, Yang CH, Sagar, Arrigoni L, Dalgaard K, Teperino R, Enders L, Selvaraj M, Ruf M, Raja SJ, Xie H, Boenisch U, Orkin SH, Lynn FC, Hoffman BG, Grün D, Vavouri T, Lempradl AM, Pospisilik JA. The Polycomb-Dependent Epigenome Controls ß Cell Dysfunction, Dedifferentiation, and Diabetes. Cell Metab. 2018 Jun 5;27(6):1294-1308.e7. doi: 10.1016/j.cmet.2018.04.013.

Posavec Marjanovic M, Hurtado-Bagès S, Lassi M, Valero V, Malinverni R, Delage H, Navarro M, Corujo D, Guberovic I, Douet J, Gama-Perez P, Garcia-Roves PM, Ahel I, Ladurner AG, Yanes O, Bouvet P, Suelves M, Teperino R, Pospisilik JA, Buschbeck M. MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD(+) consumption. Nat Struct Mol Biol. 2017 Nov;24(11):902-910. doi: 10.1038/nsmb.3481.

Chong S, Vickaryous N, Ashe A, Zamudio N, Youngson N, Hemley S, Stopka T, Skoultchi A, Matthews J, Scott HS, de Kretser D, O'Bryan M, Blewitt M, Whitelaw E. Modi?ers of epigenetic reprogramming show paternal effects in the mouse. Nat Genet. 2007 May;39(5):614-22. PubMed PMID: 17450140

Siklenka K, Erkek S, Godmann M, Lambrot R, McGraw S, La?eur C, Cohen T, Xia J, Suderman M, Hallett M, Trasler J, Peters AH, Kimmins S. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science. 2015 Nov 6;350(6261):aab2006. PubMed PMID: 26449473.

Lesch BJ, Tothova Z, Morgan EA, Liao Z, Bronson RT, Ebert BL, Page DC. Intergenerational epigenetic inheritance of cancer susceptibility in mammals. Elife. 2019 Apr 9;8. pii: e39380. doi: 10.7554/eLife.39380. PubMed PMID: 30963999

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