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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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DNA Helicases / genetics*
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DNA Helicases / metabolism
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Epigenesis, Genetic*
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Gene Expression
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Gene Knockdown Techniques
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Gluconeogenesis / genetics
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Glucose / metabolism
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Glucose-6-Phosphatase / genetics*
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Glucose-6-Phosphatase / metabolism
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Hep G2 Cells
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Histone Demethylases / antagonists & inhibitors
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Histone Demethylases / genetics
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Histone Demethylases / metabolism*
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Histones / metabolism*
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Humans
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Methylation
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Promoter Regions, Genetic
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Protein Processing, Post-Translational*
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RNA-Binding Proteins
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Transcriptional Activation
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Tranylcypromine / pharmacology
Substances
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DNA-Binding Proteins
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FUBP1 protein, human
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Histones
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RNA-Binding Proteins
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Tranylcypromine
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Histone Demethylases
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KDM1A protein, human
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Glucose-6-Phosphatase
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DNA Helicases
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Glucose