Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence

Spencer A. Haws, Deyang Yu, Cunqi Ye, Coral K. Wille, Long C. Nguyen, Kimberly A. Krautkramer, Jay L. Tomasiewicz, Shany E. Yang, Blake R. Miller, Wallace H. Liu, Kazuhiko Igarashi, Rupa Sridharan, Benjamin P. Tu, Vincent L. Cryns, Dudley W. Lamming, John M. Denu

Research output: Contribution to journalArticlepeer-review

Abstract

S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate cellular epigenetic states. This metabolism-epigenome link enables the sensitization of chromatin methylation to altered SAM abundance. However, a chromatin-wide understanding of the adaptive/responsive mechanisms that allow cells to actively protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear de novo mono-methylation of H3 Lys 9 (H3K9) at the expense of global losses in histone di- and tri-methylation. Under SAM-depleted conditions, de novo H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide the first evidence for active epigenetic adaptation and persistence to metabolic stress.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Aug 6 2019

Keywords

  • aging
  • chromatin
  • epigenetics
  • histone
  • metabolism
  • methionine
  • methylation
  • persistence
  • SAM

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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