Lew A, Rutter W J, Kennedy G C
Hormone Research Institute and the Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-0534, USA.
Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12508-12. doi: 10.1073/pnas.97.23.12508.
One of the loci responsible for genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) is the insulin-linked polymorphic region (ILPR, also known as IDDM2). This polymorphic G-rich minisatellite, located in the promoter region of the human insulin gene, comprises a variable number of tandemly repeating sequences related to ACAGGGGTGTGGGG. An interesting characteristic of the ILPR is its ability to form unusual DNA structures in vitro, presumably through formation of G-quartets. This ability to form G-quartets raises the intriguing possibility that transcriptional activity of the insulin gene may in fact be influenced by the quaternary DNA topology of the ILPR. We now show that single nucleotide differences in the ILPR known to affect insulin transcription are correlated with ability to form unusual DNA structures. Through the design and testing of two high transcriptional activity ILPR repeats, we demonstrate that both inter- and intramolecular G-quartet formation in the ILPR can influence transcriptional activity of the human insulin gene, and thus, may contribute to that portion of diabetes susceptibility attributed to the IDDM2 locus.
导致胰岛素依赖型糖尿病（IDDM）遗传易感性的基因座之一是胰岛素连锁多态性区域（ILPR，也称为IDDM2）。这个富含G的多态性微卫星位于人类胰岛素基因的启动子区域，由可变数量的与ACAGGGGTGTGGGG相关的串联重复序列组成。ILPR的一个有趣特征是它在体外形成异常DNA结构的能力，大概是通过形成G-四联体。这种形成G-四联体的能力引发了一个有趣的可能性，即胰岛素基因的转录活性实际上可能受到ILPR四级DNA拓扑结构的影响。我们现在表明，已知影响胰岛素转录的ILPR中的单核苷酸差异与形成异常DNA结构的能力相关。通过设计和测试两个具有高转录活性的ILPR重复序列，我们证明ILPR中的分子间和分子内G-四联体形成都可以影响人类胰岛素基因的转录活性，因此，可能导致归因于IDDM2基因座的那部分糖尿病易感性。
