Despite a strong genetic contribution to obesity and diabetes, genome wide association studies have identiﬁed 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 geneticindependent epigenetic mechanisms. Beside environmentally acquired epigenetic inheritance, published ﬁndings and our own preliminary data suggest that parental genetics can also control phenotypic variation in the wild-type progeny through epigenetic mechanisms. A preliminary in silico screening in our lab identiﬁed several potential non-canonical epigenetic modiﬁers. Aim of this PhD project is to further characterise one of these candidates by coupling systemic phenotyping in the mouse with state-of-the art bulk and single cell molecular proﬁlings.
- Gerlini et al. (2018). Glucose tolerance and insulin sensitivity define adipocyte transcriptional programs in human obesity. Mol Metab. 18: 42-50. (PMID: 30309776)
- Posavec et al. (2017). MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption. Nat Struct Mol Biol. 24(11): 902-910. (PMID: 29031709)
- Lu et al. (2018). The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes. Cell Metab. 5; 27(6): 1294-1308.e7. (PMID: 29754954)
- Chong et al. (2007). Modifiers of epigenetic reprogramming show paternal effects in the mouse. Nat Genet. 39(5): 614-22. (PMID: 17450140)
- Siklenka et al. (2015). Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science. 6; 350(6261). (PMID: 26449473)
- Lesch et al. (2019). Intergenerational epigenetic inheritance of cancer susceptibility in mammals. Elife. 8. pii: e39380. (PMID: 30963999)