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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0001v1 198/1/29    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wang, H.-W. Articles by Lan, M. PubMed PubMed Citation Articles by Wang, H.-W. Articles by Lan, M.

H Wang, New Orleans, United States
M Muguira, Pediatrics, The Research Institute for Children, New Orleans, United States
W Liu, New Orleans, United States
T Zhang, The Research Institute for Children, New Orleans, United States
C Chen, The Research Institute for Children, New Orleans, United States
R Aucoin, New Orleans, United States
M Breslin, New Orleans, United States
M Lan, Pediatrics, The Research Institute for Children, New Orleans, 70118, United States

Correspondence: Michael Lan, Email: mlan{at}chnola-research.org

Abstract

In this study, an INSM1-binding site in the proximal promoter sequence of the insulin gene was identified. Co-transfection of INSM1 with rat insulin I/II promoter-driven reporter genes exhibited a 40-50% inhibitory effect on 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 3-20 fold increase of promoter activity over the wild type promoter in several insulinoma cell lines. Moreover, INSM1 over-expression exhibited no inhibitory effect on the mutated insulin promoter. Chromatin immunoprecipitation assays using betaTC-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. Binding of the INSM1 to the insulin promoter could suppress approximately 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 that INSM1 is a new zinc-finger transcription factor that modulates insulin gene transcription during early pancreas development.