title: s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways.
abstract: 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.
authors: Program in Molecular Medicine, UMass Worcester, 373 Plantation Street, Worcester, MA 01605, USA.
authors: Wei
authors: W
authors: Ding
authors: Program in Molecular Medicine, UMass Worcester, 373 Plantation Street, Worcester, MA 01605, USA.
authors: Lorissa J
authors: LJ
authors: Smulan
authors: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics (CMMT) and Child & Family Research Institute (CFRI), University of British Columbia (UBC), Vancouver, BC V5Z 4H4, Canada.
authors: Nicole S
authors: NS
authors: Hou
authors: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics (CMMT) and Child & Family Research Institute (CFRI), University of British Columbia (UBC), Vancouver, BC V5Z 4H4, Canada.
authors: Stefan
authors: S
authors: Taubert
authors: School of Molecular Biosciences, Washington State University, Pullman, WA 99164-6340, USA.
authors: Jennifer L
authors: JL
authors: Watts
authors: Program in Molecular Medicine, UMass Worcester, 373 Plantation Street, Worcester, MA 01605, USA. Electronic address: amy.walker@umassmed.edu.
authors: Amy K
authors: AK
authors: Walker
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism / Q000382:microbiology; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007113:Immunity, Innate; D008099:Liver / Q000378:metabolism; D008716:Methionine Adenosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011550:Pseudomonas aeruginosa / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D006657:Histones; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; D012436:S-Adenosylmethionine; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008716:Methionine Adenosyltransferase; D020928:Mitogen-Activated Protein Kinases; C463460:Pmk-1 protein, C elegans; D048051:p38 Mitogen-Activated Protein Kinases