Histone H4 lysine 16 acetylation regulates cellular lifespan

Abstract

Cells undergoing developmental processes are characterized by persistent non-genetic alterations in chromatin, termed epigenetic changes, represented by distinct patterns of DNA methylation and histone post-translational modifications. Sirtuins, a group of conserved NAD+-dependent deacetylases or ADP-ribosyltransferases, promote longevity in diverse organisms; however, their molecular mechanisms in ageing regulation remain poorly understood. Yeast Sir2, the first member of the family to be found, establishes and maintains chromatin silencing by removing histone H4 lysine 16 acetylation and bringing in other silencing proteins. Here we report an age-associated decrease in Sir2 protein abundance accompanied by an increase in H4 lysine 16 acetylation and loss of histones at specific subtelomeric regions in replicatively old yeast cells, which results in compromised transcriptional silencing at these loci. Antagonizing activities of Sir2 and Sas2, a histone acetyltransferase, regulate the replicative lifespan through histone H4 lysine 16 at subtelomeric regions. This pathway, distinct from existing ageing models for yeast, may represent an evolutionarily conserved function of sirtuins in regulation of replicative ageing by maintenance of intact telomeric chromatin. The sirtuins, conserved NAD+-dependent deacetylases or ADP-ribosyltransferases, promote longevity in many organisms, though the mechanisms involved are poorly understood. For example, the yeast sirtuin Sir2 is known to deacetylate the lysine 16 residue in histone H4, but it was not clear whether this relates to Sir2's anti-ageing role. Dang et al. now report an age-associated decrease in Sir2 protein abundance that is associated with increased H4 lysine 16 acetylation and a loss of histones, causing compromised transcriptional silencing at specific subtelomeric regions in replicatively old yeast cells. This histone acetylation pathway, distinct from existing ageing models for yeast, may represent an evolutionarily conserved function of sirtuins in regulation of replicative ageing through the maintenance of intact telomeric chromatin. Yeast Sir2 deacetylates histone H4 lysine 16 and is known to have a role in ageing, but the exact mechanism is not known. Here, an age-associated decrease in Sir2 abundance is shown to be accompanied by an increase in H4 lysine 16 acetylation and loss of histones in replicatively old yeast cells, resulting in compromised transcriptional silencing.