title: Suppression of gluconeogenic gene expression by LSD1-mediated histone demethylation.
abstract: Aberrant gluconeogenic gene expression is associated with diabetes, glycogen storage disease, and liver cancer. However, little is known how these genes are regulated at the chromatin level. In this study, we investigated in HepG2 cells whether histone demethylation is a potential mechanism. We found that knockdown or pharmacological inhibition of histone demethylase LSD1 causes remarkable transcription activation of two gluconeogenic genes, FBP1 and G6Pase, and consequently leads to increased de novo glucose synthesis and decreased intracellular glycogen content. Mechanistically, LSD1 occupies the promoters of FBP1 and G6Pase, and modulates their H3K4 dimethylation levels. Thus, our work identifies an epigenetic pathway directly governing gluconeogenic gene expression, which might have important implications in metabolic physiology and diseases.
authors.affiliation: Program in Gene Function and Expression and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Dongning
authors.initials: D
authors.lastname: Pan
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Mao
authors.forename: Yong-Xu
authors.initials: YX
authors.lastname: Wang
mesh_terms: D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism; D056945:Hep G2 Cells; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D016601:RNA-Binding Proteins; D015533:Transcriptional Activation; D014191:Tranylcypromine / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D006657:Histones; D016601:RNA-Binding Proteins; D014191:Tranylcypromine; D056466:Histone Demethylases; C495195:KDM1A protein, human; D005952:Glucose-6-Phosphatase; D004265:DNA Helicases; D005947:Glucose