Histones H2A, H2B, H3 and H4, the protein components of the nucleosome core particle, are subject to numerous chemically distinct post-translational modifications. In terms of function and regulation, the best characterized amongst these is reversible acetylation of lysine residues in the conserved histone amino-terminal tails. Histone acetylation is mediated by lysine acetylases (KATs) and reversed by histone deacetylases (HDACs), and controlled to a large extent by mechanisms that impinge on these enzymes (1
). This report concerns physiological regulation of histone acetylation in budding yeast in response to glucose, the preferred carbon source of this organism (3
Our experiments extend previous studies in which it was shown by immunoblotting analysis of total cellular proteins that overall H3/H4 acetylation declines as yeast cells progress into stationary phase (SP) in response to nutrient depletion from their environment (4
). Conversely, SP cells inoculated into fresh medium give rise to an expanding population with a relatively high level of histone acetylation (data not shown). Although glucose refeeding in SP does not trigger entry into S phase, it does elicit gross morphological changes characteristic of preparation for re-proliferation (6
). We therefore reasoned that glucose might also induce overall H3/H4 acetylation. Here, we show that glucose refeeding indeed triggers robust acetylation of nucleosomal H3 (at K9, 14, 18, 27) and H4 (at K5, 8, 12) in SP cells. For simplicity, we refer to these events collectively as ‘H3/H4 acetylation’.
Physiological resetting of overall histone acetylation uncoupled from replication is well documented in mammalian cells. For example, H3 K9 and H4 acetylation are induced prior to S phase in mitogenically stimulated B and T cells (7
), H4 acetylation is induced one day after the onset of embryonic stem cell differentiation (9
), H3/H4 acetylation is induced in cells of the hippocampus and cortex during neuronal rewiring (10
), and H3 K9 acetylation is induced in the course of epigenetic reprogramming in the germ line (11
). Despite the abundant evidence that overall histone acetylation is subject to physiological regulation in non-replicating cells, little is known about the mechanisms of this regulation. We therefore further characterized glucose stimulation overall histone acetylation in SP yeast cells.
What mechanism could account for glucose induction of acetylation in SP cells? A straightforward and compelling model is suggested by two principles in chromatin biology which are widely appreciated and generally accepted. The first is that physiological cues can trigger signal transduction events which cause transcriptional induction of some genes, and repression of others. The second is that induction of transcription is typically accompanied by increased acetylation of chromatin (1
). In yeast, it is well established that signaling pathways activated by glucose can drive reprogramming of transcription (3
), and while our work was ongoing, it was reported that almost 1400 genes are induced when SP cells are fed glucose (13
). We further show here that glucose induction of H3/H4 acetylation largely depends on two KATs which play a pivotal role in transcription in yeast and higher eukaryotes (14–17
). These are Gcn5, which acetylates H3, and Esa1, which acetylates H4 (1
The scenario suggested by previous studies (and consistent with prevailing views in the field) is that glucose induction of overall acetylation in SP cells is simply the sum of targeted acetylation events associated with pervasive induction of transcription driven by glucose-dependent signaling. Surprisingly, this is not the case. Glucose induction of H3/H4 acetylation in SP yeast cells is principally due to direct metabolic induction of KATs which act globally throughout chromatin.