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

8 Scopus citations

Abstract

S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate epigenetic states and subsequent gene expression. This metabolism-epigenome link sensitizes chromatin methylation to altered SAM abundance, yet the mechanisms that allow organisms to adapt and 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 mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone di- and tri-methylation. Under SAM-depleted conditions, 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 evidence for an adaptive response that enables epigenetic persistence to metabolic stress.

Original languageEnglish (US)
Pages (from-to)210-223.e8
JournalMolecular cell
Volume78
Issue number2
DOIs
StatePublished - Apr 16 2020

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence'. Together they form a unique fingerprint.

Cite this