DNA methylation and Sp1 binding determine the tissue-specific transcriptional activity of the mouse Abcc6 promoter
DNA methylation and Sp1 binding determine the tissue-specific transcriptional activity of the mouse Abcc6 promoter
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DOI：
10.1016/j.bbrc.2006.12.151
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发表时间：
2007-03-02
影响因子：
3.1
通讯作者：
Le Saux, Olivier
中科院分区：
文献类型：
--
作者：
Douet, Vanessa;Heller, Matthew B.;Le Saux, Olivier
编码ABCC6蛋白的基因是多药耐药相关蛋白（MRP）的ABC转运蛋白，主要在肝脏和肾脏中表达。ABCC6突变导致弹性假黄瘤（PXE）表型的发生。PXE是一种以弹性纤维钙化为特征的隐性疾病，可导致皮肤、血管和眼部的临床表现。ABCC6和啮齿类同源物ABCC6的生理功能尚不清楚，它们与弹性纤维的确切关系也只是猜测。尽管有一些研究集中在ABCC6/ ABCC6的转录调控上，但赋予ABCC6/ ABCC6表达组织特异性的分子信号并没有很好地定义。在本报告中，我们测定了小鼠Abcc6启动子甲基化水平在低表达（尾巴和皮肤）、中表达（肾脏）和高表达（肝脏）组织中的表达水平。我们观察到高水平和中等水平的甲基化与低水平的Abcc6表达相关。此外，我们确定Abcc6近端启动子区域的CpG甲基化会干扰Sp1转录因子的结合，从而抑制Sp1依赖性的转激活。因此，我们的数据提供了第一个直接证据，表明表观遗传机制调节转录因子Sp1与近端启动子的结合，并参与小鼠Abcc6基因的组织特异性表达控制。(c) 2006爱思唯尔公司版权所有。
The gene encoding the ABCC6 protein, an ABC transporter of the multidrug resistance-associated protein (MRP), is mainly expressed in liver and kidney. Mutations in ABCC6 are responsible for the development of the pseudoxanthoma elasticum (PXE) phenotype. PXE is a recessive disease characterized by the calcification of elastic fibers resulting in dermal, vascular, and ocular clinical manifestations. The physiological function of ABCC6 and the rodent orthologs Abcc6 is unknown and their precise relationship to elastic fibers is only a matter of speculation. Despite several studies focused on the transcriptional regulation of ABCC6/Abcc6, the molecular signals conferring the tissue-specificity to the ABCC6/Abcc6 expression are not well defined. In this report, we determined the level of the mouse Abcc6 promoter methylation in tissues with low level of expression (tail extremity and skin), intermediate (kidney), and high level of expression (liver). We observed that high and moderate levels of methylation correlated with low levels of Abcc6 expression. Moreover, we determined that CpG methylation of the Abcc6 proximal promoter region was interfering with the binding of the Sp1 transcription factor thereby inhibiting Sp1-dependent transactivation. Thus, our data provide the first direct evidence that an epigenetic mechanism regulates the binding of transcription factor Sp1 to the proximal promoter and participates in the tissue-specific expression control of the mouse Abcc6 gene. (c) 2006 Elsevier Inc. All rights reserved.