Impact of chronic inflammation on epigenetic reprogramming of hematopoietic stem cells during ageing – INCHROMAGE

Our objective is to define the impact of chronic inflammation on the chromatin structure of hematopoietic stem cells (HSC) during ageing and to explore epigenetic-based strategies to limit these damaging effects.
Advancing age is characterized by a progressive decline in the physiology and function of adult tissues. Notably, major changes occur in the hematopoietic system leading to a higher rate of anaemia and reduced immune responses in the elderly. These changes exert significant effects on the health of the elderly, contributing to increased morbidity and mortality arising from infectious diseases as well as to a higher incidence of cancer. Numerous studies indicate that functional alterations of HSCs are at the root of these age-related hematological defects. Indeed, the ability of these stem cells to generate immune-competent B and T lymphocytes declines with age and aged HSC exhibit a myeloid-biased differentiation potential. While the molecular mechanisms underlying these changes in HSC function are not fully understood, both epigenetic changes and chronic inflammation have been implicated as drivers of HSC aging. In this proposal we will explore the links between these two potential causes of ageing in the hematopoietic system.
Our preliminary observations have indicated a decline with age of the chromatin-dependent transcriptional silencing machineries based on histone H3 lysine methylation (H3K9me) and HP1 binding in HSCs, while in parallel, we have shown that the H3K9me3 / HP1 axis regulates the amplitude of the inflammatory response in different cell types. We therefore propose to:
- Investigate the effect of chronic inflammation on the H3K9me / HP1 axis in HSCs
- Determine the impact of an impaired H3K9me / HP1 axis on the perpetuation and amplification of inflammation.
- Explore epigenetic-based strategies to limit the damage inflicted by inflammation on HSCs by reinforcing H3K9me/HP1-mediated repression.
To carry out this project INCHROMAGE brings together a team of experts specialising in ageing of HSC, epigenetics, and inflammation. The work will be based on original mouse models of chronic inflammation that will allow us to investigate the impact of sustained exposure of HSC to low level inflammation on epigenetic pathways in an in vivo context. These studies will improve understanding of the ties connecting inflammation to ageing, will give new insights on the effects of inflammation on chromatin structure and cell fate, and will evaluate the potential of candidate epidrugs in limiting these effects.