Hepatic nuclear factor 1-α directs nucleosomal hyperacetylation to its tissue-specific transcriptional targets
Hepatic nuclear factor 1-α directs nucleosomal hyperacetylation to its tissue-specific transcriptional targets
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DOI：
10.1128/mcb.21.9.3234-3243.2001
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发表时间：
2001-05-01
影响因子：
5.3
通讯作者：
Ferrer, J
中科院分区：
文献类型：
--
作者：
Párrizas, M;Maestro, MA;Ferrer, J
编码肝核因子1- α (hnf1 - α)的基因突变导致人类糖尿病的一种亚型，由选择性胰腺细胞功能障碍引起。我们分析了缺乏hnf1 - α的小鼠，以研究该蛋白如何在体内控制β细胞特异性转录。我们发现hnf1 - α对于胰胰岛素生成细胞中glut2葡萄糖转运蛋白和l型丙酮酸激酶（plklr）基因的表达至关重要，而在肝、肾或十二指肠组织中，在缺乏hnf1 - α的情况下，glut2和pldr的表达得以维持。然而，hnf1 - α在胰岛细胞和肝细胞中都占据内源性glut2和plklr启动子。然而，它对于胰岛中glut2和plklr启动子核小体中的组蛋白的高乙酰化是必不可少的，而不是在肝细胞中，在缺乏hnf1 - α的情况下，glut2和plklr染色质仍保持高乙酰化。相比之下，苯丙氨酸羟化酶启动子仅在肝组织中需要hnf1 - α来进行转录活性和局部组蛋白超乙酰化。因此，在胰腺β细胞或肝细胞中，不同的hnf1 - α靶基因对hnf1 - α有不同的需求。结果表明，HNF1-alpha在多种组织中占据靶基因启动子，但仅在细胞和启动子特异性环境中发挥转录激活的专性作用，在这种情况下，HNF1-alpha需要招募组蛋白乙酰化酶活性。这些发现提供了基于活体哺乳动物系统的遗传证据，证明单个激活因子对于指导核小体高乙酰化到转录靶点至关重要。
Mutations in the gene encoding hepatic nuclear factor 1-alpha (HNF1-alpha) cause a subtype of human diabetes resulting from selective pancreatic beta -cell dysfunction. We have analyzed mice lacking HNF1-alpha to study how this protein controls beta -cell-specific transcription in vivo. We show that HNF1-alpha is essential for the expression of glut2 glucose transporter and L-type pyruvate kinase (pklr) genes in pancreatic insulin-producing cells, whereas in liver, kidney, or duodenum tissue, glut2 and pldr expression is maintained in the absence of HNF1-alpha. HNF1-alpha nevertheless occupies the endogenous glut2 and pklr promoters in both pancreatic islet and liver cells. However, it is indispensable for hyperacetylation of histones in glut2 and pklr promoter nucleosomes in pancreatic islets but not in liver cells, where glut2 and pklr chromatin remains hyperacetylated in the absence of HNF1-alpha. In contrast, the phenylalanine hydroxylase promoter requires HNF1-alpha for transcriptional activity and localized histone hyperacetylation only in liver tissue. Thus, different HNF1-alpha target genes have distinct requirements for HNF1-alpha in either pancreatic beta -cells or liver cells. The results indicate that HNF1-alpha occupies target gene promoters in diverse tissues but plays an obligate role in transcriptional activation only in cellular- and promoter-specific contexts in which it is required to recruit histone acetylase activity. These findings provide genetic evidence based on a live mammalian system to establish that a single activator can be essential to direct nucleosomal hyperacetylation to transcriptional targets.