Suppression of gluconeogenic gene expression by LSD1-mediated histone demethylation

• Published in: PloS one Vol. 8; no. 6; p. e66294
• Main Authors: Pan, Dongning, Mao, Chunxiao, Wang, Yong-Xu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.06.2013; Public Library of Science (PLoS)
• Subjects: Aberration; Biology; Cancer; Cell growth; Chromatin; Demethylation; Diabetes; Diabetes mellitus; Disease; DNA Helicases - genetics; DNA Helicases - metabolism; DNA methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enzymes; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Gene Expression; Gene Knockdown Techniques; Genes; Genetic aspects; Gluconeogenesis - genetics; Glucose; Glucose - metabolism; Glucose-6-Phosphatase - genetics; Glucose-6-Phosphatase - metabolism; Glycogen; Hep G2 Cells; Histone Demethylases - antagonists & inhibitors; Histone Demethylases - genetics; Histone Demethylases - metabolism; Histones - metabolism; Humans; Kinases; Leukemia; Liver; Liver cancer; Liver diseases; Medicine; Metabolism; Methylation; Pharmacology; Promoter Regions, Genetic; Protein Processing, Post-Translational; RNA-Binding Proteins; Rodents; Stem cells; Transcription (Genetics); Transcription activation; Transcriptional Activation; Tranylcypromine - pharmacology; Tumors; Type 2 diabetes; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0066294

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.