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Hong-Wei Wang The Research Institute for Children, Departments of Pediatrics and Genetics, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room 2211, New Orleans, Louisiana 70118, USA
The Research Institute for Children, Departments of Pediatrics and Genetics, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room 2211, New Orleans, Louisiana 70118, USA

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Michelle Muguira The Research Institute for Children, Departments of Pediatrics and Genetics, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room 2211, New Orleans, Louisiana 70118, USA

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Wei-Dong Liu The Research Institute for Children, Departments of Pediatrics and Genetics, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room 2211, New Orleans, Louisiana 70118, USA
The Research Institute for Children, Departments of Pediatrics and Genetics, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room 2211, New Orleans, Louisiana 70118, USA

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Tao Zhang The Research Institute for Children, Departments of Pediatrics and Genetics, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room 2211, New Orleans, Louisiana 70118, USA
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Chiachen Chen The Research Institute for Children, Departments of Pediatrics and Genetics, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room 2211, New Orleans, Louisiana 70118, USA

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Rebecca Aucoin The Research Institute for Children, Departments of Pediatrics and Genetics, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room 2211, New Orleans, Louisiana 70118, USA

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Mary B Breslin The Research Institute for Children, Departments of Pediatrics and Genetics, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room 2211, New Orleans, Louisiana 70118, USA
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Michael S Lan The Research Institute for Children, Departments of Pediatrics and Genetics, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room 2211, New Orleans, Louisiana 70118, USA
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In this study, an insulinoma-associated antigen-1 (INSM1)-binding site in the proximal promoter sequence of the insulin gene was identified. The co-transfection of INSM1 with rat insulin I/II promoter-driven reporter genes exhibited a 40–50% inhibitory effect on the reporter activity. Mutational experiments were performed by introducing a substitution, GG to AT, into the INSM1 core binding site of the rat insulin I/II promoters. The mutated insulin promoter exhibited a three- to 20-fold increase in the promoter activity over the wild-type promoter in several insulinoma cell lines. Moreover, INSM1 overexpression exhibited no inhibitory effect on the mutated insulin promoter. Chromatin immunoprecipitation assays using βTC-1, mouse fetal pancreas, and Ad-INSM1-transduced human islets demonstrated that INSM1 occupies the endogenous insulin promoter sequence containing the INSM1-binding site in vivo. The binding of the INSM1 to the insulin promoter could suppress ∼50% of insulin message in human islets. The mechanism for transcriptional repression of the insulin gene by INSM1 is mediated through the recruitment of cyclin D1 and histone deacetylase-3 to the insulin promoter. Anti-INSM1 or anti-cyclin D1 morpholino treatment of fetal mouse pancreas enhances the insulin promoter activity. These data strongly support the view that INSM1 is a new zinc-finger transcription factor that modulates insulin gene transcription during early pancreas development.

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