Chromatin rejuvenation and DNA damage responses during ageing of human chromosomes
Description: Ageing represents an inevitable endpoint in metazoans and is characterized by multisystemic functional decline. This is often linked to the accumulation of DNA damage along chromosomes with time. Elevated reactive oxygen species (ROS) in particular, are produced as a byproduct of cellular metabolism and considered among the main drivers of the pathophysiology of ageing and age-related disorders. It would be expected that the process of ageing and the induction of genotoxic stress should impact all levels of gene regulation, however, little is known about the differential effects that distinct stimulants of DNA damage cause in the multiple levels of genome architecture and function. Thus, an in-depth elucidation of the oxidative damage-to-chromosome structure relationship at the molecular level is needed.
A recent study led by the proposed host lab (Debes et al., Nature, 2023) demonstrated that ageing is characterized by abnormally high transcription elongation speeds in multiple cell types, tissues, and species, and that overexpression of histone proteins not only restores the kinetics of transcription to physiological levels, but also restricts the emergence of various ageing features in human cells. The inherent link between chromatin and 3D genome structure suggests that this histone-driven “rejuvenation” of ageing cells is bound to changes in the spatial architecture of chromosomes. Still, it remains unclear how these chromatin-based interventions can counter the ageing processes
Putting these two together, I propose a study of the effects of chromatin rejuvenation on 3D chromosome architecture as well as on the genome’s ability to cope with oxidative damage. To this end, I will combine ultra-resolution 3D genomics with nascent epigenome mapping in aged (senescent) and “rejuvenated” primary human cells before and after inducing either chronic (low doses, prolonged treatment) or acute (high doses, one exposure) oxidative DNA damage. In a next step, these experiments can be complemented by in vivo dissection of rejuvenated mouse tissue at the single cell level. I expect these experiments to shed light on the molecular mechanisms and regulatory principles behind chromosomal stress responses during ageing.
In conclusion, this research program will provide new insights into the crucial role of chromatin architecture during ageing, while deciphering differences in the ability of aged and rejuvenated cells to respond to oxidative stress induction. Thus, possible novel approaches for preventing and managing late-life disease by epigenome regulation might emerge.
Funder: Human Frontier Science Program
Amount:
Funding type: award
Start date: 2024-10-15
End date: 2027-10-14
Investigator: Anastasios Liakos
Institution: Alexander Fleming Biomedical Sciences Research Center
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: LT0034/2024-L
OpenAlex ID: G1756096095