Active gene repression by the Egr2•NAB complex during peripheral nerve myelination
Active gene repression by the Egr2•NAB complex during peripheral nerve myelination
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DOI：
10.1074/jbc.m803330200
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发表时间：
2008-06-27
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：
Mager, Gennifer M.;Ward, Rebecca M.;Svaren, John
在雪旺细胞周围神经髓鞘形成过程中，需要Egr2/Krox20反激活子激活许多髓鞘相关基因。然而，最近的研究表明，Egr2不仅激活周围神经髓鞘形成所需的基因，还可能参与基因抑制。NAB （NGFI-A/ egr结合）协同抑制因子与Egr2相互作用，是髓磷脂形成的适当协调所必需的。因此，NAB蛋白可以介导一些Egr2靶基因的抑制，尽管在髓鞘形成过程中Egr2或NAB蛋白的直接抑制尚未被证实。为了确定NAB共抑制在Egr2基因抑制中的生理作用，我们测试了Egr2中心点NAB复合物是否直接抑制特定靶基因。对nab调节基因的筛选发现了几个（包括Id2， Id4和Rad）在周围神经髓鞘形成过程中下降。对成髓鞘坐骨神经的体内染色质免疫沉淀分析显示，Egr2和NAB2与Id2、Id4和Rad启动子的发育相关，因为它们在成髓鞘过程中受到抑制。此外，NAB2通过与核小体重塑和去乙酰化酶染色质重塑复合体的染色质解旋酶dna结合蛋白4 （CHD4）亚基相互作用来抑制转录，并且我们证明了CHD4在体内以发育调节的方式占据NAB2抑制的启动子。这些结果说明了周围神经髓鞘形成遗传调控的一个新方面，表明Egr2在髓鞘形成过程中与NAB共抑制因子一起直接抑制基因。此外，发现Id2的抑制可以增强Mpz（髓鞘蛋白零）表达的激活。
The Egr2/Krox20 transactivator is required for activation of many myelin-associated genes during peripheral nerve myelination by Schwann cells. However, recent work has indicated that Egr2 not only activates genes required for peripheral nerve myelination but may also be involved in gene repression. The NAB (NGFI-A/Egr-binding) corepressors interact with Egr2 and are required for proper coordination of myelin formation. Therefore, NAB proteins could mediate repression of some Egr2 target genes, although direct repression by Egr2 or NAB proteins during myelination has not been demonstrated. To define the physiological role of NAB corepression in gene repression by Egr2, we tested whether the Egr2 center dot NAB complex directly repressed specific target genes. A screen for NAB-regulated genes identified several (including Id2, Id4, and Rad) that declined during the course of peripheral nerve myelination. In vivo chromatin immunoprecipitation analysis of the myelinating sciatic nerve was used to show developmental association of both Egr2 and NAB2 on the Id2, Id4, and Rad promoters as they were repressed during the myelination process. In addition, NAB2 represses transcription by interaction with the chromodomain helicase DNA-binding protein 4 (CHD4) subunit of the nucleosome remodeling and deacetylase chromatin remodeling complex, and we demonstrate that CHD4 occupies NAB-repressed promoters in a developmentally regulated manner in vivo. These results illustrate a novel aspect of genetic regulation of peripheral nerve myelination by showing that Egr2 directly represses genes during myelination in conjunction with NAB corepressors. Furthermore, repression of Id2 was found to augment activation of Mpz (myelin protein zero) expression.