title: Transcriptional regulation of the albumin gene depends on the removal of histone methylation marks by the FAD-dependent monoamine oxidase lysine-specific demethylase 1 in HepG2 human hepatocarcinoma cells.
abstract: Lysine-specific demethylase (LSD) 1 is an FAD-dependent demethylase that catalyzes the removal of methyl groups from lysine-4 in histone H3, thereby mediating gene repression. Here we tested the hypothesis that riboflavin deficiency causes a loss of LSD1 activity in HepG2 human hepatocarcinoma cells, leading to an accumulation of lysine-4-dimethylated histone H3 (H3K4me2) marks in the albumin promoter and aberrant upregulation of albumin expression. Cells were cultured in riboflavin-defined media providing riboflavin at concentrations representing moderately deficient (3.1 nmol/L), sufficient (12.6 nmol/L), and supplemented (301 nmol/L) cells in humans for 7 d. The efficacy of treatment was confirmed by assessing glutathione reductase activity and concentrations of reduced glutathione as markers of riboflavin status. LSD activity was 21% greater in riboflavin-supplemented cells compared with riboflavin-deficient and -sufficient cells. The loss of LSD activity was associated with a gain in the abundance of H3K4me2 marks in the albumin promoter; the abundance of H3K4me2 marks was ∼170% higher in riboflavin-deficient cells compared with sufficient and supplemented cells. The abundance of the repression mark, K9-trimethylated histone H3, was 38% lower in the albumin promoter of riboflavin-deficient cells compared with the other treatment groups. The expression of albumin mRNA was aberrantly increased by 200% in riboflavin-deficient cells compared with sufficient and supplemented cells. In conclusion, riboflavin deficiency impairs gene regulation by epigenetic mechanisms, mediated by a loss of LSD1 activity.
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE.
authors.forename: Dandan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE jzempleni2@unl.edu.
authors.forename: Janos
authors.initials: J
authors.lastname: Zempleni
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D063185:Epigenetic Repression; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008995:Monoamine Oxidase / Q000378:metabolism; D009994:Osmolar Concentration; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D012256:Riboflavin / Q000378:metabolism; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism*; D000075462:Serum Albumin, Human; D015533:Transcriptional Activation
chemical_list: C422455:ALB protein, human; D015415:Biomarkers; D006657:Histones; D012333:RNA, Messenger; D012709:Serum Albumin; D005182:Flavin-Adenine Dinucleotide; D056466:Histone Demethylases; D008995:Monoamine Oxidase; C495195:KDM1A protein, human; D005980:Glutathione Reductase; D005978:Glutathione; D008239:Lysine; D012256:Riboflavin; D000075462:Serum Albumin, Human
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