Saccharomyces cerevisiae TORC1 controls histone acetylation by signaling through the sit4/PP6 phosphatase to regulate sirtuin deacetylase nuclear accumulation

Jason J. Workman, Hongfeng Chen, Ronald Laribee

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 sit4D 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 (tco89D) to hydroxyurea and arsenic can be reversed by combining tco89D with either hst3D, hst4D, or sit4D. Surprisingly, while hst3D or hst4D rescues the sensitivity tco89D has to low concentrations of the TORC1 inhibitor rapamycin, sit4D 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.

Original languageEnglish (US)
Pages (from-to)1733-1746
Number of pages14
JournalGenetics
Volume203
Issue number4
DOIs
StatePublished - Aug 1 2016

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Acetylation
Phosphoric Monoester Hydrolases
Histones
Saccharomyces cerevisiae
Epigenomics
mechanistic target of rapamycin complex 1
Food
Hydroxyurea
Arsenic
Sirolimus
Proteins
Nitrogen
Yeasts
Cell Proliferation
Amino Acids

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Saccharomyces cerevisiae TORC1 controls histone acetylation by signaling through the sit4/PP6 phosphatase to regulate sirtuin deacetylase nuclear accumulation. / Workman, Jason J.; Chen, Hongfeng; Laribee, Ronald.

In: Genetics, Vol. 203, No. 4, 01.08.2016, p. 1733-1746.

Research output: Contribution to journalArticle

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