title: Saccharomyces cerevisiae TORC1 Controls Histone Acetylation by Signaling Through the Sit4/PP6 Phosphatase to Regulate Sirtuin Deacetylase Nuclear Accumulation.
abstract: The epigenome responds to changes in the extracellular environment, yet how this information is transmitted to the epigenetic regulatory machinery is unclear. Using a Saccharomyces cerevisiae yeast model, we demonstrate that target of rapamycin complex 1 (TORC1) signaling, which is activated by nitrogen metabolism and amino acid availability, promotes site-specific acetylation of histone H3 and H4 N-terminal tails by opposing the activity of the sirtuin deacetylases Hst3 and Hst4 TORC1 does so through suppression of the Tap42-regulated Sit4 (PP6) phosphatase complex, as sit4Δ rescues histone acetylation under TORC1-repressive conditions. We further demonstrate that TORC1 inhibition, and subsequent PP6 activation, causes a selective, rapid, nuclear accumulation of Hst4, which correlates with decreased histone acetylation. This increased Hst4 nuclear localization precedes an elevation in Hst4 protein expression, which is attributed to reduced protein turnover, suggesting that nutrient signaling through TORC1 may limit Hst4 nuclear accumulation to facilitate Hst4 degradation and maintain histone acetylation. This pathway is functionally relevant to TORC1 signaling since the stress sensitivity of a nonessential TORC1 mutant (tco89Δ) to hydroxyurea and arsenic can be reversed by combining tco89Δ with either hst3Δ, hst4Δ, or sit4Δ Surprisingly, while hst3Δ or hst4Δ rescues the sensitivity tco89Δ has to low concentrations of the TORC1 inhibitor rapamycin, sit4Δ fails to do so. These results suggest Sit4 provides an additional function necessary for TORC1-dependent cell growth and proliferation. Collectively, this study defines a novel mechanism by which TORC1 suppresses a PP6-regulated sirtuin deacetylase pathway to couple nutrient signaling to epigenetic regulation.
authors.affiliation: Department of Pathology and Laboratory Medicine and the University of Tennessee Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Jason J
authors.identifier: 0000-0002-9071-5207
authors.initials: JJ
authors.lastname: Workman
authors.affiliation: Department of Pathology and Laboratory Medicine and the University of Tennessee Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine and the University of Tennessee Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 rlaribee@uthsc.edu.
authors.forename: R Nicholas
authors.identifier: 0000-0003-4519-4470
authors.initials: RN
authors.lastname: Laribee
mesh_terms: D000107:Acetylation / Q000187:drug effects; D002453:Cell Cycle / Q000235:genetics; D044127:Epigenesis, Genetic; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D006655:Histone Deacetylases / Q000235:genetics*; D006657:Histones / Q000235:genetics; D009154:Mutation; D054648:Protein Phosphatase 2 / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics
chemical_list: D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; C561842:TORC1 protein complex, S cerevisiae; D014157:Transcription Factors; D054648:Protein Phosphatase 2; C104343:SIT4 protein, S cerevisiae; C512517:Hst3 protein, S cerevisiae; C512518:Hst4 protein, S cerevisiae; D006655:Histone Deacetylases; D020123:Sirolimus
keywords: Sit4; epigenetic; histone acetylation; sirtuins; target of rapamycin