Molecular mechanisms of cellular response to age-associated chromatin changes

PROJECT SUMMARY Profound changes in chromatin occur in aged cells and tissues. These changes, such as altered histone modifications and chromatin conformation, lead to loss of heterochromatin, reduced nucleosome stability, and aberrant transcription, all of which have been causally linked to the aging process. Using yeast strains with reduced histone dosage, a model mimicking the situation of aged cells, we uncovered a cellular response to such chromatin defects, named chromatin architectural defects (CAD) response or simply chromatin stress response. Like cellular stress to heat and oxidation where moderate levels of stress can lead to hormesis, a beneficial effect, activating CAD response with moderate chromatin defects extends lifespan, offering a new intervention strategy to antagonize aging and age-related diseases. However, many mechanistic details of this response remain unexplored. This project will focus on these mechanistic questions. Does the CAD response directly mitigate age-associated chromatin changes and defects, such as disrupted heterochromatin, loss of transcription silencing and cryptic transcription? TOR inhibition is critical for the longevity effect of CAD response. How does the CAD response crosstalk with other TOR-related stress response pathways? In particular, does the CAD response interact with Isw2-regulated longevity-promoting stress responses? How does CAD response interact with metabolic changes? What are the regulators and effectors of CAD response? Importantly, how does the previously identified CAD response transcription factor Gis1 function to activate the transcriptional response? Addressing these questions pertaining to detailed molecular mechanisms will help characterize CAD response with molecular regulators and effectors, physiological effects to the cell, and relationships with other stress response and metabolic pathways. These mechanistic details will establish CAD response as a novel form of stress response with hormetic effects that promote longevity.