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Molecular and Cellular Biology, October 2008, p. 6373-6383, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00413-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Histone Deacetylase Inhibitors Modify Pancreatic Cell Fate Determination and Amplify Endocrine Progenitors{triangledown} ,{dagger}

Cécile Haumaitre,* Olivia Lenoir, and Raphaël Scharfmann

INSERM U845, Centre de Recherche Croissance et Signalisation, Université Paris Descartes, Faculté de Médecine, Hôpital Necker, 75015 Paris, France

Received 12 March 2008/ Returned for modification 20 May 2008/ Accepted 4 August 2008

During pancreas development, transcription factors play critical roles in exocrine and endocrine differentiation. Transcriptional regulation in eukaryotes occurs within chromatin and is influenced by posttranslational histone modifications (e.g., acetylation) involving histone deacetylases (HDACs). Here, we show that HDAC expression and activity are developmentally regulated in the embryonic rat pancreas. We discovered that pancreatic treatment with different HDAC inhibitors (HDACi) modified the timing and determination of pancreatic cell fate. HDACi modified the exocrine lineage via abolition and enhancement of acinar and ductal differentiation, respectively. Importantly, HDACi treatment promoted the NGN3 proendocrine lineage, leading to an increased pool of endocrine progenitors and modified endocrine subtype lineage choices. Interestingly, treatments with trichostatin A and sodium butyrate, two inhibitors of both class I and class II HDACs, enhanced the pool of β cells. These results highlight the roles of HDACs at key points in exocrine and endocrine differentiation. They show the powerful use of HDACi to switch pancreatic cell determination and amplify specific cellular subtypes, with potential applications in cell replacement therapies in diabetes.

* Corresponding author. Mailing address: INSERM U845, Centre de Recherche Croissance et Signalisation, Université Paris Descartes, 156 rue de Vaugirard, Faculté de Médecine, 75015 Paris, France. Phone: 33 140 615584. Fax: 33 143 060443. E-mail: cecile.haumaitre-sarron{at}inserm.fr

{triangledown} Published ahead of print on 18 August 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2008, p. 6373-6383, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00413-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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