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Molecular and Cellular Biology, October 2009, p. 5264-5276, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00526-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Nucleosome Binding Protein HMGN3 Modulates the Transcription Profile of Pancreatic β Cells and Affects Insulin Secretion {triangledown}

Tetsuya Ueda,1 Takashi Furusawa,1,{dagger} Toshihiro Kurahashi,1,{dagger} Lino Tessarollo,2 and Michael Bustin1*

Protein Section, Laboratory of Metabolism,1 Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208922

Received 23 April 2009/ Returned for modification 19 May 2009/ Accepted 23 July 2009

Improper glucose-stimulated insulin secretion from pancreatic β 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 β cells and that in mice, loss of HMGN3 impairs glucose-stimulated insulin secretion and leads to a diabetic phenotype. In pancreatic β 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 β 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.

* Corresponding author. Mailing address: Protein Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-5234. Fax: (301) 496-8419. E-mail: bustin{at}helix.nih.gov

{triangledown} Published ahead of print on 3 August 2009.

{dagger} Equal contributions.

Molecular and Cellular Biology, October 2009, p. 5264-5276, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00526-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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