This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Google Scholar
Right arrow Articles by Servitja, J.-M.
Right arrow Articles by Ferrer, J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Servitja, J.-M.
Right arrow Articles by Ferrer, J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2009, p. 2945-2959, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01389-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Hnf1{alpha} (MODY3) Controls Tissue-Specific Transcriptional Programs and Exerts Opposed Effects on Cell Growth in Pancreatic Islets and Liver{triangledown} ,{dagger}

Joan-Marc Servitja,1,2 Miguel Pignatelli,3,{ddagger} Miguel Ángel Maestro,1,2 Carina Cardalda,1 Sylvia F. Boj,1 Juanjo Lozano,3 Enrique Blanco,3 Amàlia Lafuente,4 Mark I. McCarthy,5 Lauro Sumoy,3 Roderic Guigó,3 and Jorge Ferrer1,2*

Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain,1 CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain,2 Bioinformatics and Genomics Programme, Centre de Regulació Genòmica (CRG), Barcelona, Spain,3 Departament de Farmacologia, Universitat de Barcelona, Barcelona, Spain,4 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom5

Received 3 September 2008/ Returned for modification 29 October 2008/ Accepted 2 March 2009

Heterozygous HNF1A mutations cause pancreatic-islet β-cell dysfunction and monogenic diabetes (MODY3). Hnf1{alpha} is known to regulate numerous hepatic genes, yet knowledge of its function in pancreatic islets is more limited. We now show that Hnf1a deficiency in mice leads to highly tissue-specific changes in the expression of genes involved in key functions of both islets and liver. To gain insights into the mechanisms of tissue-specific Hnf1{alpha} regulation, we integrated expression studies of Hnf1a-deficient mice with identification of direct Hnf1{alpha} targets. We demonstrate that Hnf1{alpha} can bind in a tissue-selective manner to genes that are expressed only in liver or islets. We also show that Hnf1{alpha} is essential only for the transcription of a minor fraction of its direct-target genes. Even among genes that were expressed in both liver and islets, the subset of targets showing functional dependence on Hnf1{alpha} was highly tissue specific. This was partly explained by the compensatory occupancy by the paralog Hnf1β at selected genes in Hnf1a-deficient liver. In keeping with these findings, the biological consequences of Hnf1a deficiency were markedly different in islets and liver. Notably, Hnf1a deficiency led to impaired large-T-antigen-induced growth and oncogenesis in β cells yet enhanced proliferation in hepatocytes. Collectively, these findings show that Hnf1{alpha} governs broad, highly tissue-specific genetic programs in pancreatic islets and liver and reveal key consequences of Hnf1a deficiency relevant to the pathophysiology of monogenic diabetes.

* Corresponding author. Mailing address: Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Villarroel 170, Barcelona 08036, Spain. Phone: 34-93-2275400, ext. 3028. Fax: 34-93-4516638. E-mail: jferrer{at}clinic.ub.es

{triangledown} Published ahead of print on 30 March 2009.

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

{ddagger} Present address: Institut Cavanilles de Biodiversitat i Biologia Evolutiva, Universitat de València, and CIBER de Epidemiología y Salud Pública, València, Spain.

Molecular and Cellular Biology, June 2009, p. 2945-2959, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01389-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Li, H., Dong, B., Park, S. W., Lee, H.-S., Chen, W., Liu, J. (2009). Hepatocyte Nuclear Factor 1{alpha} Plays a Critical Role in PCSK9 Gene Transcription and Regulation by the Natural Hypocholesterolemic Compound Berberine. J. Biol. Chem. 284: 28885-28895 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»