Hnf1alpha (MODY3) controls tissue-specific transcriptional programs and exerts opposed effects on cell growth in pancreatic islets and liver.
Heterozygous HNF1A mutations cause pancreatic-islet beta-cell dysfunction and monogenic diabetes (MODY3). Hnf1alpha 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 Hnf1alpha regulation, we integrated expression studies of Hnf1a-deficient mice with identification of direct Hnf1alpha targets. We demonstrate that Hnf1alpha can bind in a tissue-selective manner to genes that are expressed only in liver or islets. We also show that Hnf1alpha 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 Hnf1alpha was highly tissue specific. This was partly explained by the compensatory occupancy by the paralog Hnf1beta 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 beta cells yet enhanced proliferation in hepatocytes. Collectively, these findings show that Hnf1alpha 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.
Servitja
Joan-Marc
JM
Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Pignatelli
Miguel
M
Maestro
Miguel Angel
MA
Cardalda
Carina
C
Boj
Sylvia F
SF
Lozano
Juanjo
J
Blanco
Enrique
E
Lafuente
Amàlia
A
McCarthy
Mark I
MI
Sumoy
Lauro
L
Guigó
Roderic
R
Ferrer
Jorge
J
D024506:5' Flanking Region / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D019295:Computational Biology; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D016678:Genome / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000172:deficiency / Q000378:metabolism*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D014158:Transcription, Genetic
D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D051539:Hepatocyte Nuclear Factor 1-beta