Stress-induced chromatin remodelling in health and disease

The human genome´s accessibility is tightly controlled by its organisation into chromatin.

Cellular stresses, like DNA damage and protein misfolding, trigger transient chromatin remodelling, enabling essential responses such as DNA repair and stress-protective gene activation.

This process is orchestrated by histone chaperones and nucleosome remodelling enzymes, and its dysfunction is linked to aging and neurological diseases.I aim to unveil the molecular mechanisms governing stress-induced chromatin plasticity.

I will focus on SPT2, a poorly characterized histone chaperone that I have recently implicated in the cellular stress response.

Notably, SPT2 dynamically interacts with proteins mutated in neurological diseases upon DNA damage and proteotoxic stress.

Using advanced proteomics, targeted protein degradation, and microscopy, I will elucidate the function of SPT2 and its interacting partners in promoting transcriptional stress responses in human cells, including neurons.

Finally, using quantitative temporal proteomics I will generate a comprehensive resource of the neuronal chromatin responses to stress.By unravelling the mechanisms of stress-induced chromatin remodelling and its connection to neurological health, this project holds significant promise.

It will provide crucial insights into how the genome dynamically adapts to stress and how these responses contribute to neuronal protection and disease prevention.