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

Mol Cell. 2020 Apr 16;78(2):210-223.e8. doi: 10.1016/j.molcel.2020.03.004. Epub 2020 Mar 23.


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.

Keywords: SAM; aging; chromatin; epigenetics; histone; metabolism; methionine; methylation; persistence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Chromatin / genetics
  • Cytoplasm / genetics
  • Cytoplasm / metabolism
  • DNA Methylation / genetics*
  • Epigenesis, Genetic / genetics
  • Gene Expression Regulation / genetics
  • HCT116 Cells
  • Heterochromatin / genetics*
  • Heterochromatin / metabolism
  • Histone-Lysine N-Methyltransferase / genetics
  • Histones / genetics
  • Humans
  • Metabolome / genetics*
  • Methionine / genetics
  • Mice
  • Protein Processing, Post-Translational / genetics
  • Proteomics / methods
  • S-Adenosylmethionine / metabolism*


  • Chromatin
  • Heterochromatin
  • Histones
  • S-Adenosylmethionine
  • Methionine
  • Histone-Lysine N-Methyltransferase