title: PRMT5 modulates the metabolic response to fasting signals.
abstract: Under fasting conditions, increases in circulating glucagon maintain glucose balance by promoting hepatic gluconeogenesis. Triggering of the cAMP pathway stimulates gluconeogenic gene expression through the PKA-mediated phosphorylation of the cAMP response element binding (CREB) protein and via the dephosphorylation of the latent cytoplasmic CREB regulated transcriptional coactivator 2 (CRTC2). CREB and CRTC2 activities are increased in insulin resistance, in which they promote hyperglycemia because of constitutive induction of the gluconeogenic program. The extent to which CREB and CRTC2 are coordinately up-regulated in response to glucagon, however, remains unclear. Here we show that, following its activation, CRTC2 enhances CREB phosphorylation through an association with the protein arginine methyltransferase 5 (PRMT5). In turn, PRMT5 was found to stimulate CREB phosphorylation via increases in histone H3 Arg2 methylation that enhanced chromatin accessibility at gluconeogenic promoters. Because depletion of PRMT5 lowers hepatic glucose production and gluconeogenic gene expression, these results demonstrate how a chromatin-modifying enzyme regulates a metabolic program through epigenetic changes that impact the phosphorylation of a transcription factor in response to hormonal stimuli.
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Tsai
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Naomi
authors.initials: N
authors.lastname: Goebel
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004734:Energy Metabolism / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D005215:Fasting / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D005943:Gluconeogenesis / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases; D013058:Mass Spectrometry; D008745:Methylation; D051379:Mice; D010766:Phosphorylation; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C115163:CREB1 protein, human; C493245:CRTC2 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D008156:Luciferases; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases