Histone Methylation Has Dynamics Distinct from Those of Histone Acetylation in Cell Cycle Reentry from Quiescence

Abstract

Cell growth is attuned to nutrient availability to sustain homeostatic biosynthetic processes. In unfavorable environments, cells enter a nonproliferative state termed quiescence but rapidly return to the cell cycle once conditions support energetic needs. Changing cellular metabolite pools are proposed to directly alter the epigenome via histone acetylation. Here we studied the relationship between histone modification dynamics and the dramatic transcriptional changes that occur during nutrient-induced cell cycle reentry from quiescence in the yeast Saccharomyces cerevisiae. SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry showed that histone methylation-in contrast to histone acetylation-is surprisingly static during quiescence exit. Chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) revealed genomewide shifts in histone acetylation at growth and stress genes as cells exit quiescence and transcription dramatically changes. Strikingly, however, the patterns of histone methylation remain intact. We conclude that the functions of histone methylation and acetylation are remarkably distinct during quiescence exit: acetylation rapidly responds to metabolic state, while methylation is independent. Thus, the initial burst of growth gene reactivation emerging from quiescence involves dramatic increases of histone acetylation but not of histone methylation. C ells constantly sense and integrate environmental cues to control proliferative growth, but the underlying molecular mechanisms remain unclear. Eukaryotic cells, including adult stem cells, typically exist in a state of growth arrest-quiescence-that is distinguished by two principal qualities: quiescent cells both safeguard cell identity and retain the ability to resume proliferation once external cues become favorable (1-3). Remarkably little is known about the molecular processes that mediate quiescence exit and the transition to proliferative growth, which requires massive changes in cell metabolism and reprogramming of global gene expression (4-6).Recent evidence suggests that the metabolic state is a principle regulator of quiescence establishment and exit via epigenetic changes that alter gene expression (7-9). A clear example is that nutrient-induced increases in acetyl coenzyme A (acetyl-CoA) pools promote chromatin acetylation and growth gene transcription (10, 11). Rhythmic fluctuations of acetyl-CoA levels are characteristic of the metabolic cycle that budding yeast cells enter during growth under nutrient-limiting conditions. In such a milieu, recurrent bursts of acetyl-CoA production by the acetyl-CoA synthase Acs2p have been linked to increased histone acetylation and growth gene expression, indicating a functional connection between metabolic state and gene transcription via chromatin acetylation (10). Indeed, studies in both the yeast Saccharomyces cerevisiae and activated lymphocytes indicate that glucose-induced histone acetylation is a critical and highly conserved driver of quie...

Global Promoter Targeting of a Conserved Lysine Deacetylase for Transcriptional Shutoff during Quiescence Entry

“…Histone acetylation is generally thought to reflect transcriptional status, with high acetylation associated with transcribed regions and hypoacetylation corresponding to more repressed regions (Grunstein, 1997). We find that a global reduction in histone acetylation occurs after Q entry, when maximum transcriptional repression is observed (Figure 2E), as reported for mixed populations of stationary phase yeast (Mews et al, 2014). Together, the global changes in chromatin structure are consistent with the genome-wide transcriptional shutdown we observe above (Figure 1).…”

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

“…Short-term nutrient deprivation resulted in alterations in all 3 histone marks (Figure 4(a)). As expected, the most pronounced effect was observed on the histone acetylation status, which has been demonstrated to be more dynamically regulated than methylation [27]. Increased H3K4me3, H3K27ac, and H3K56ac alterations directly correlated with increased mRNA expression (Figure 4(b)).…”

A Metabolic Function for Phospholipid and Histone Methylation

“…Blocking methylation at H3K79 also led to substantial increases in H3K36 methylation (Figure 6B and S6A). H3K36 methylation is also one of the more dynamic histone methylation marks (Mews et al, 2014), perhaps facilitation the utilization of this site as a sink.…”