Mechanisms of mutual functional interactions between HNF-4α and HNF-1α revealed by mutations that cause maturity onset diabetes of the young
Mechanisms of mutual functional interactions between HNF-4α and HNF-1α revealed by mutations that cause maturity onset diabetes of the young
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DOI：
10.1152/ajpgi.00431.2005
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发表时间：
2006-03-01
影响因子：
4.5
通讯作者：
Simon, TC
中科院分区：
文献类型：
--
作者：
Rowley, CW;Staloch, LJ;Simon, TC
肝核因子（HNF）-4 α和HNF-1 α是物理和功能相互作用的关键内胚层转录调节因子。HNF-4 α和HNF-1 α协同激活具有两种因子结合位点的基因，而抑制性相互作用发生在仅具有一种因子结合位点的调控序列处。肝脏脂肪酸结合蛋白基因（Fabp 1）具有两种因子的结合位点，染色质沉淀试验用于证明HNF-4 α在协同转录激活期间增加HNF-1 α Fabp 1启动子占用。HNF-4 P2启动子含有HNF-1但不含HNF-4结合位点，HNF-4 α抑制HNF-1 α HNF-4 P2活化并降低启动子HNF-1 α占用率。载脂蛋白C III（APOC 3）启动子含有HNF-4但不含HNF-1结合位点，HNF-1 α抑制HNF-4 α APOC 3激活并降低HNF-4 α启动子占用率。青年成熟型糖尿病（MODY）以及肝脏脂质代谢缺陷是由HNF-4 α或HNF-1 α突变引起的。我们发现MODY错义突变体R127 W HNF-4 α保留了野生型个体Fabp 1的活化，并且与HNF-1 α的结合比野生型HNF-4 α更好，但不与HNF-1 α合作或增加HNF-1 α Fabp 1启动子的占有率. R127 W突变体在抑制HNF-1 α激活HNF 4 P2和降低HNF-1 α启动子占有率方面也有缺陷。HNF-1 α R131 QMODY突变体也保留了野生型Fabp 1的活化，并与HNF-4 α以及野生型结合，但在抑制HNF-4 α APOC 3活化和降低HNF-4 α启动子占有率方面都有缺陷.这些结果表明HNF-1 α- HNF-4 α功能性相互作用是通过调节因子启动子占据来实现的，并且有缺陷的因子-因子相互作用可能导致MODY表型。
Hepatic nuclear factor (HNF)-4 alpha and HNF-1 alpha are key endodermal transcriptional regulators that physically and functionally interact. HNF-4 alpha and HNF-1 alpha cooperatively activate genes with binding sites for both factors, whereas suppressive interactions occur at regulatory sequences with a binding site for only one factor. The liver fatty acid binding protein gene (Fabp1) has binding sites for both factors, and chromatin precipitation assays were utilized to demonstrate that HNF-4 alpha increased HNF-1 alpha Fabp1 promoter occupancy during cooperative transcriptional activation. The HNF4 P2 promoter contains a HNF-1 but not HNF-4 binding site, and HNF-4 alpha suppressed HNF-1 alpha HNF4 P2 activation and decreased promoter HNF-1 alpha occupancy. The apolipoprotein C III (APOC3) promoter contains a HNF-4 but not HNF-1 binding site, and HNF-1 alpha suppressed HNF-4 alpha APOC3 activation and decreased HNF-4 alpha promoter occupancy. Maturity onset diabetes of the young ( MODY) as well as defects in hepatic lipid metabolism result from mutations in either HNF-4 alpha or HNF-1 alpha. We found that MODY missense mutant R127W HNF-4 alpha retained wildtype individual Fabp1 activation and bound to HNF-1 alpha better than wild- type HNF-4 alpha, yet did not cooperate with HNF-1 alpha or increase HNF-1 alpha Fabp1 promoter occupancy. The R127W mutant was also defective in both suppressing HNF-1 alpha activation of HNF4 P2 and decreasing HNF-1 alpha promoter occupancy. The HNF-1 alpha R131Q MODY mutant also retained wild- type Fabp1 activation and bound to HNF-4 alpha as well as the wild type but was defective in both suppressing HNF-4 alpha APOC3 activation and decreasing HNF-4 alpha promoter occupancy. These results suggest HNF-1 alpha- HNF-4 alpha functional interactions are accomplished by regulating factor promoter occupancy and that defective factor- factor interactions may contribute to the MODY phenotype.