Hnf1α (MODY3) Controls Tissue-Specific Transcriptional Programs and Exerts Opposed Effects on Cell Growth in Pancreatic Islets and Liver
Hnf1α (MODY3) Controls Tissue-Specific Transcriptional Programs and Exerts Opposed Effects on Cell Growth in Pancreatic Islets and Liver
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DOI：
10.1128/mcb.01389-08
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发表时间：
2009-06-01
影响因子：
5.3
通讯作者：
Ferrer, Jorge
中科院分区：
文献类型：
--
作者：
Servitja, Joan-Marc;Pignatelli, Miguel;Ferrer, Jorge
HNF1A杂合突变导致胰岛β细胞功能障碍和单基因糖尿病(MODY3)。已知HNF1α调节多种肝脏基因，但对其在胰岛中的功能了解较少。我们现在发现，小鼠缺乏HNF1A会导致与胰岛和肝脏关键功能相关的基因表达发生高度组织特异性的变化。为了深入了解组织特异性Hnf1α调控的机制，我们将HNF1a基因缺陷小鼠的表达研究与直接Hnf1α靶标的鉴定相结合。我们证明了Hnf1α可以以组织选择性的方式与仅在肝脏或胰岛表达的基因结合。我们还表明，Hnf1α只对其直接靶基因的一小部分转录是必不可少的。即使在肝脏和胰岛都表达的基因中，表现出对Hnf1α功能依赖性的靶子子集也具有高度的组织特异性。这在一定程度上是由于HNF1a缺陷型肝脏中特定基因上Hnf1β的代偿性占据。与这些发现一致的是，HNF1A缺乏在胰岛和肝脏中的生物学后果明显不同。值得注意的是，HNF1A缺乏导致大T抗原诱导的β细胞生长和肿瘤形成减弱，但促进了肝细胞的增殖。总而言之，这些发现表明，HNF1α控制着广泛的、高度组织特异性的胰岛和肝脏遗传程序，并揭示了HNF1a缺乏与单基因糖尿病的病理生理相关的关键后果。
Heterozygous HNF1A mutations cause pancreatic-islet beta-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 Hnf1 beta 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 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.