s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways

Cell Metab. 2015 Oct 6;22(4):633-45. doi: 10.1016/j.cmet.2015.07.013. Epub 2015 Aug 27.


s-adenosylmethionine (SAM) is the sole methyl donor modifying histones, nucleic acids, and phospholipids. Its fluctuation affects hepatic phosphatidylcholine (PC) synthesis or may be linked to variations in DNA or histone methylation. Physiologically, low SAM is associated with lipid accumulation, tissue injury, and immune responses in fatty liver disease. However, molecular connections among SAM limitation, methyltransferases, and disease-associated phenotypes are unclear. We find that low SAM can activate or attenuate Caenorhabditis elegans immune responses. Immune pathways are stimulated downstream of PC production on a non-pathogenic diet. In contrast, distinct SAM-dependent mechanisms limit survival on pathogenic Pseudomonas aeruginosa. C. elegans undertakes a broad transcriptional response to pathogens and we find that low SAM restricts H3K4me3 at Pseudomonas-responsive promoters, limiting their expression. Furthermore, this response depends on the H3K4 methyltransferase set-16/MLL. Thus, our studies provide molecular links between SAM and innate immune functions and suggest that SAM depletion may limit stress-induced gene expression.

Publication types

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

MeSH terms

  • Animals
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans / microbiology
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / metabolism
  • Immunity, Innate*
  • Liver / metabolism
  • Methionine Adenosyltransferase / antagonists & inhibitors
  • Methionine Adenosyltransferase / genetics
  • Methionine Adenosyltransferase / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylcholines / metabolism
  • Promoter Regions, Genetic
  • Pseudomonas aeruginosa / physiology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • S-Adenosylmethionine / metabolism*
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Caenorhabditis elegans Proteins
  • Histones
  • Phosphatidylcholines
  • RNA, Small Interfering
  • S-Adenosylmethionine
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Methionine Adenosyltransferase
  • Mitogen-Activated Protein Kinases
  • Pmk-1 protein, C elegans
  • p38 Mitogen-Activated Protein Kinases