Induction of Myelin Protein Zero by Early Growth Response 2 through Upstream and Intragenic Elements
Induction of Myelin Protein Zero by Early Growth Response 2 through Upstream and Intragenic Elements
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DOI：
10.1074/jbc.m109.022426
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发表时间：
2009-07-24
影响因子：
4.8
通讯作者：
Svaren, John
中科院分区：
文献类型：
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作者：
Jang, Sung-Wook;Svaren, John
髓鞘蛋白零(MPZ)基因编码周围神经系统中髓鞘的主要成分，该基因的突变会导致人类周围髓鞘疾病。MPZ基因的表达受两个协调雪旺细胞发育的主要反式激活因子控制：Egr2/Krox20和Sox10。我们对髓鞘周围神经进行的体内芯片分析发现，Egr2相互作用的主要部位位于MPZ基因第一内含子内，类似于转录起始点上游的5kb。此外，Egr2结合位点显示了许多与增强子元件相关的特征。有趣的是，Egr2的上游结合部位位于差异转录的琥珀酸脱氢酶C基因的近端，但SDHC的表达并不受Egr2介导的MPZ大量诱导的影响。Egr2结合位点的存在极大地促进了MPZ的诱导，去除Egr2结合位点显著降低了来自MPZ位点的构建体的转基因表达。SOX10还被发现与上游区域相关，并且它的结合是Egr2介导的这一末端调节区激活所必需的。我们的研究结果强调，MPZ的外周神经特异性表达主要受上游和内含子相关调控元件的调节。总体而言，这些结果提供了对Egr2在其天然染色体背景下调节MPZ基因的作用和活性的基因座范围的分析。
The Mpz (myelin protein zero) gene codes for the principal component of myelin in the peripheral nervous system, and mutations in this gene cause human peripheral myelinopathies. Expression of the Mpz gene is controlled by two major transactivators that coordinate Schwann cell development: Egr2/Krox20 and Sox10. Our in vivo ChIP-chip analysis in myelinating peripheral nerve identified major sites of Egr2 interaction within the first intron of the Mpz gene and similar to 5 kb upstream of the transcription start site. In addition, the sites of Egr2 binding display many of the hallmarks associated with enhancer elements. Interestingly, the upstream Egr2 binding sites lie proximal to the divergently transcribed succinate dehydrogenase C gene, but Sdhc expression was not affected by the massive induction of Mpz mediated by Egr2. Mpz induction was greatly enhanced in the presence of the Egr2 binding sites, and removal of them markedly diminished transgenic expression of a construct derived from the Mpz locus. Sox10 was also found to be associated with the upstream region, and its binding was required for Egr2-mediated activation in this distal regulatory region. Our findings highlight that peripheral nerve-specific expression of Mpz is primarily regulated by both upstream and intron-associated regulatory elements. Overall, these results provide a locus-wide analysis of the role and activity of Egr2 in regulation of the Mpz gene within its native chromosomal context.