Cellular environment controls the dynamics of histone H3 lysine 56 acetylation in response to DNA damage in mammalian cells

ABSTRACT

Epigenetic changes play a crucial role in sensing signals and responding to fluctuations in the extracellularenvironment. How the cellular micro-environment affects DNA damage response signalling in chromatincontext is not extensively studied. Histone acetylation is dynamic and very sensitive to changes in theextracellular environment. Existing literature on H3 lysine 56 acetylation (H3K56ac) levels upon DNA damagein mammals presents a conflicting picture. The occurrence of both increased and decreased H3K56ac uponDNA damage in our experiments led us to investigate the role of the micro-environment on H3K56ac. Here,we show that the global levels of H3K56ac increase as cells grow from low density to high density whileSIRT1 and SIRT6 expression decrease. Additionally, rising lactic acid levels increase H3K56ac. Our resultsshow that cell density and accumulation of metabolites affect dynamics of H3K56ac in response to DNAdamage. Upon DNA damage, H3K56ac increases in low density cells with low initial acetylation, whileacetylation decreases in high cell density cells. These results highlight that H3K56ac levels upon DNA damageare dependent on the metabolites in the extracellular milieu which impact chromatin structure by regulatingchromatin modifying enzymes. Accumulation of lactic acid at high cell density reflects conditions similar to thetumour micro-environment. As H3K56ac increases in tumours, lactic acid and low pH might alter H3K56ac intumours, leading to deregulated gene expression, contributing to tumour progression.