From epidemiological studies and experimental data, we know that chronic diseases accelerate the ageing process, suggesting that ageing and chronic diseases share common mechanisms. In human and mouse models, ageing is generally associated with a physiological increase in lipid accumulation in non-adipose tissues including the liver [Slawik, M. and A.J. Vidal-Puig, 2006]. This aged phenotype in liver closely mirrors the main features of the most common chronic disease in liver, non-alcoholic fatty liver disease (NAFLD). Chronic liver diseases affect the metabolic function of the liver and non-alcoholic fatty liver has been identified as a potential cause of drug-induced liver injury in elderly [Gong, Z., et al. 2017].
We will use mouse models for NAFLD as well as human samples (from biobanks) to investigate the effect of chronic accumulation of lipids in the liver at the single-cell level. We will focus on single-cell DNA methylation, scATAC-seq and scRNA-seq and the development of a computational approach to integrate and harmonize those datasets [Clark, S.J., et al., 2018; Buenrostro, J.D., et al., 2015; Chen, X., et al., 2018; Martinez-Jimenez, C.P., et al., 2017]. The goal is to map the epigenetic features that correlates with changes in the hepatic transcriptional network in NAFLD and ageing, and use those epigenetic signatures as predictive marks of accelerated ageing.
- Slawik, M. and A.J. Vidal-Puig (2006). Lipotoxicity, overnutrition and energy metabolism in aging. Ageing Res Rev 5(2): p. 144-64.
- Gong, Z., et al. (2017). Hepatic lipid metabolism and non-alcoholic fatty liver disease in aging. Mol Cell Endocrinol.
- Clark, S.J., et al. (2018). scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells. Nat Commun 9(1): p. 781.
- Buenrostro, J.D., et al. (2015). Single-cell chromatin accessibility reveals principles of regulatory variation. Nature 523(7561): p. 486-90.
- Chen, X., et al. (2018). A rapid and robust method for single cell chromatin accessibility profiling. Nat Commun 9(1): p. 5345.
- Martinez-Jimenez, C.P., et al. (2017). Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science 355(6332): p. 1433-1436.