title: Metabolic control of the epigenome in systemic Lupus erythematosus.
abstract: Epigenetic mechanisms are proposed to underlie aberrant gene expression in systemic lupus erythematosus (SLE) that results in dysregulation of the immune system and loss of tolerance. Modifications of DNA and histones require substrates derived from diet and intermediary metabolism. DNA and histone methyltransferases depend on S-adenosylmethionine (SAM) as a methyl donor. SAM is generated from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase (MAT), a redox-sensitive enzyme in the SAM cycle. The availability of B vitamins and methionine regulate SAM generation. The DNA of SLE patients is hypomethylated, indicating dysfunction in the SAM cycle and methyltransferase activity. Acetyl-CoA, which is necessary for histone acetylation, is generated from citrate produced in mitochondria. Mitochondria are also responsible for de novo synthesis of flavin adenine dinucleotide (FAD) for histone demethylation. Mitochondrial oxidative phosphorylation is the dominant source of ATP. The depletion of ATP in lupus T cells may affect MAT activity as well as adenosine monophosphate (AMP) activated protein kinase (AMPK), which phosphorylates histones and inhibits mechanistic target of rapamycin (mTOR). In turn, mTOR can modify epigenetic pathways including methylation, demethylation, and histone phosphorylation and mediates enhanced T-cell activation in SLE. Beyond their role in metabolism, mitochondria are the main source of reactive oxygen intermediates (ROI), which activate mTOR and regulate the activity of histone and DNA modifying enzymes. In this review we will focus on the sources of metabolites required for epigenetic regulation and how the flux of the underlying metabolic pathways affects gene expression.
authors.affiliation: Division of Rheumatology, Departments of Medicine, Microbiology and Immunology, and Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, College of Medicine , Syracuse, NY , USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Oaks
authors.forename: Andras
authors.initials: A
authors.lastname: Perl
mesh_terms: D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000276:immunology / Q000378:metabolism; D006657:Histones / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D012436:S-Adenosylmethionine / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D006657:Histones; D012436:S-Adenosylmethionine; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: Epigenetics; SLE; genetics; metabolism