The nucleosome binding protein HMGN3 modulates the transcription profile of pancreatic beta cells and affects insulin secretion.
Improper glucose-stimulated insulin secretion from pancreatic beta cells is a major factor in the onset of type 2 diabetes. We now report that HMGN3, a nuclear protein that binds to nucleosomes and affects chromatin function, is highly expressed in beta cells and that in mice, loss of HMGN3 impairs glucose-stimulated insulin secretion and leads to a diabetic phenotype. In pancreatic beta cells, loss of HMGN3 affects the transcription of several genes involved in glucose-stimulated insulin secretion, including that of the Glut2 glucose transporter. Chromatin immunoprecipitation reveals that HMGN3 and the transcription factor PDX1 mutually reinforce their specific binding to the chromatin in the promoter of the Glut2 gene, thereby regulating GLUT2 protein levels in pancreatic islets and in beta cells. Our results identify a new regulator of glucose homeostasis and demonstrate a link between the activity of a nucleosome binding structural protein and the regulation of insulin secretion.
Ueda
Tetsuya
T
Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Furusawa
Takashi
T
Kurahashi
Toshihiro
T
Tessarollo
Lino
L
Bustin
Michael
M
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D024001:HMGN Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009707:Nucleosomes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014158:Transcription, Genetic
D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D024001:HMGN Proteins; C543894:HMGN3 protein, human; C532059:HMGN3 protein, mouse; D007328:Insulin; D009707:Nucleosomes; C495680:SLC2A2 protein, human; C495682:Slc2a2 protein, mouse