Paquette J, Giannoukakis N, Polychronakos C, Vafiadis P, Deal C
Department of Pediatrics, Ste-Justine Hospital Research Center, Montreal, Quebec H3T 1C5, Canada.
J Biol Chem. 1998 Jun 5;273(23):14158-64. doi: 10.1074/jbc.273.23.14158.
The minisatellite DNA polymorphism consisting of a variable number of tandem repeats (VNTR) at the human INS (insulin gene) 5'-flanking region has demonstrated allelic effects on insulin gene transcription in vitro and has been associated with the level of insulin gene expression in vivo. We now show that this VNTR also has effects on the nearby insulin-like growth factor II gene (IGF2) in human placenta in vivo and in the HepG2 hepatoma cell line in vitro. We show that higher steady-state IGF2 mRNA levels are associated with shorter alleles (class I) than the longer class III alleles in term placentae. In vitro, reporter gene activity was greater from reporter gene constructs with IGF2 promoter 3 in the presence of class I alleles than from those with class III. Taken together with the documented transcriptional effects on the insulin gene, we propose that the VNTR may act as a long range control element affecting the expression of both INS and IGF2. The localization of a type 1 diabetes susceptibility locus (IDDM2) to the VNTR itself suggests that either or both of these genes may be involved in the biologic effects of IDDM2.
人类胰岛素基因（INS）5'侧翼区由可变数量串联重复序列（VNTR）组成的小卫星DNA多态性已在体外证明对胰岛素基因转录具有等位基因效应，并且与体内胰岛素基因的表达水平有关。我们现在表明，这种VNTR在体内的人胎盘中以及在体外的HepG2肝癌细胞系中，对附近的胰岛素样生长因子II基因（IGF2）也有影响。我们发现，在足月胎盘中，与较长的III类等位基因相比，较高的稳态IGF2 mRNA水平与较短的等位基因（I类）相关。在体外，在I类等位基因存在的情况下，具有IGF2启动子3的报告基因构建体的报告基因活性高于具有III类等位基因的构建体。结合已记录的对胰岛素基因的转录作用，我们提出VNTR可能作为一种远距离控制元件，影响INS和IGF2的表达。1型糖尿病易感位点（IDDM2）定位于VNTR本身，这表明这些基因中的一个或两个可能参与IDDM2的生物学效应。
