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 genome-wide 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.

ACKNOWLEDGMENTS

We thank J. Rabinowitz and his laboratory for their generous help and Wenyun Lu in particular for the SRM analysis. We thank Leila Afjehi-Sadat for sharing both her insight and the benzoic anhydride peptide preparation protocol. We thank the IDOM Functional Genomics Core Sequencing Facility for RNA-seq and ChIP-seq.

This work was supported by an NIA P01 grant (P01AG031862) and Ellison Foundation Senior Scholar award to S.L.B.