Servitja Joan-Marc, Pignatelli Miguel, Maestro Miguel Angel, Cardalda Carina, Boj Sylvia F, Lozano Juanjo, Blanco Enrique, Lafuente Amàlia, McCarthy Mark I, Sumoy Lauro, Guigó Roderic, Ferrer Jorge
Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Mol Cell Biol. 2009 Jun;29(11):2945-59. doi: 10.1128/MCB.01389-08. Epub 2009 Mar 16.
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.
杂合型HNF1A突变会导致胰岛β细胞功能障碍和单基因糖尿病（MODY3）。已知Hnf1alpha可调节众多肝脏基因，但其在胰岛中的功能了解较为有限。我们现在表明，小鼠中Hnf1a的缺失会导致胰岛和肝脏关键功能相关基因表达发生高度组织特异性变化。为深入了解组织特异性Hnf1alpha调控机制，我们将Hnf1a缺陷小鼠的表达研究与直接Hnf1alpha靶标的鉴定相结合。我们证明Hnf1alpha能够以组织选择性方式结合仅在肝脏或胰岛中表达的基因。我们还表明，Hnf1alpha仅对其一小部分直接靶基因的转录至关重要。即使在肝脏和胰岛中都表达的基因中，显示对Hnf1alpha功能依赖性的靶标子集也是高度组织特异性的。这部分是由于在Hnf1a缺陷肝脏中，旁系同源物Hnf1beta在选定基因上的代偿性占据所致。与这些发现一致，Hnf1a缺陷在胰岛和肝脏中的生物学后果明显不同。值得注意的是，Hnf1a缺陷导致β细胞中大型T抗原诱导的生长和肿瘤发生受损，但肝细胞增殖增强。总体而言，这些发现表明Hnf1alpha在胰岛和肝脏中控制广泛的、高度组织特异性的遗传程序，并揭示了与单基因糖尿病病理生理学相关的Hnf1a缺陷的关键后果。
