Epigenetic Regulation of Nuclear cGAS Activity in Aging-Related Inflammation

Chronic inflammation is a hallmark of aging and plays a key role in the development of numerous neurological disorders. In the mammalian innate immune system, cyclic GMP-AMP synthase (cGAS) detects foreign or damaged endogenous DNA, synthesizes the second messenger 2’3’-cGAMP, and activates STING to promote the production of type-I interferons and interferon-stimulated genes. While recent studies suggest that activation of nuclear cGAS is critical in aging-related inflammation and neurodegeneration, the mechanisms by which nuclear cGAS is activated to drive chronic inflammation during aging remain poorly understood. Our preliminary findings reveal an unexpected link between chromatin regulation and cGAS activation, potentially explaining how cGAS contributes to aging-induced chronic inflammation. We discovered that cGAS, which is predominantly enriched in the nucleus and bound to nucleosomes in an inactive state, is released and activated by histone H4 N-terminal tail acetylation. Moreover, we found that BRD4, a known reader of H4 acetylation, binds acetylated H4-containing nucleosomes and further enhances cGAS activation. Since increased H4 acetylation is a hallmark of aging, we propose that aging-related histone hyperacetylation leads to the release and activation of nuclear cGAS, driving chronic inflammation and contributing to age-related diseases. Our central hypothesis is that specific patterns of histone H4 acetylation, along with their reader proteins, represent a novel regulatory mechanism that unleashes and activates chromatin-bound cGAS, contributing to inflammation and aging. If validated, these findings would introduce a new paradigm for understanding how nuclear cGAS drives aging and could pave the way for therapeutic strategies targeting H4 acetylation and BRD4 to control inflammation during aging. To test this hypothesis, we have assembled a multidisciplinary team with expertise in structural biology, biophysics, biochemistry, cell biology, chromatin biology, and epigenetics. Together, we will pursue three specific aims: (1) decipher the histone H4 acetylation patterns that regulate the activation of nucleosome-bound cGAS, (2) elucidate how H4 acetylation readers activate nucleosome-bound cGAS, and (3) investigate the physiological roles of H4 acetylation-dependent nuclear cGAS activation in cellular senescence and aging. This research, spanning from atomic structures and mechanistic insights to genetic models and animal pathology, offers an innovative concept and framework to advance our understanding of nuclear cGAS regulation in chronic inflammation. The potential findings could uncover a new paradigm at the intersection of epigenetics, innate immunity, and aging, and facilitate the development of cGAS-targeted therapies for age-related disorders. Project Number: 1R01AG095618-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Qi Zhang (+1 co-PI) | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $647,866 | Activity Code: R01 | Study Section: Macromolecular Structure and Function A Study Section[MSFA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11219454