This Article Full Text (PDF) Other Versions of this Article: MCB.00413-08v1 28/20/6373    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 Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Haumaitre, C. Articles by Scharfmann, R. PubMed PubMed Citation Articles by Haumaitre, C. Articles by Scharfmann, R.

 Previous Article  |  Next Article 

Mol. Cell. Biol. doi:10.1128/MCB.00413-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors

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

^* To whom correspondence should be addressed. Email: cecile.haumaitre{at}necker.fr.

	Abstract

During pancreas development, transcription factors play critical roles in exocrine and endocrine differentiation. Transcriptional regulation in eukaryotes occurs within chromatin and is influenced by post-translational histone modifications (e.g. acetylation) involving histone deacetylases (HDACs). Here, we showed 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 pro-endocrine lineage leading to an increased pool of endocrine progenitors and modified endocrine sub-type lineage choices. Interestingly, treatments with Trichostatin A and sodium butyrate, two inhibitors of both class I and class II HDACs, enhanced the pool of -cells. These results highlight the role 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 sub-types, with potential applications in cell replacement therapies in diabetes.