Epigenetic programming of mu-opioid receptor gene in mouse brain is regulated by MeCP2 and Brg1 chromatin remodelling factor.
Epigenetic programming of mu-opioid receptor gene in mouse brain is regulated by MeCP2 and Brg1 chromatin remodelling factor.
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DOI：
10.1111/j.1582-4934.2008.00535.x
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发表时间：
2009-09
影响因子：
5.3
通讯作者：
Loh HH
中科院分区：
文献类型：
--
作者：
Hwang CK;Song KY;Kim CS;Choi HS;Guo XH;Law PY;Wei LN;Loh HH
吗啡作为止痛药的药理作用主要是通过μ-阿片受体(MOR)介导的。除极少数例外，MOR在发生阿片类药物活动的大脑区域表达。MOR这种独特的空间表达的基础仍然不确定。最近，我们报道了MOR启动子的DNA甲基化在调节P19细胞MOR中起重要作用。在这项研究中，我们证明了MOR在显微解剖的小鼠脑区域中的差异表达与DNA甲基化和组蛋白修饰相一致。在MOR阴性细胞中，去甲基化药物或组蛋白脱乙酰酶抑制剂可以诱导MOR基因的表达，提示MOR基因可以在表观遗传控制下沉默。甲基-CpG-结合蛋白2(MeCP2)在小脑的体内相互作用增强，其中MOR启动子高甲基化，在所有被测脑区中MOR的表达最低。MeCP2与Rett综合征密切相关，Rett综合征是一种神经发育障碍。我们还建立了新的证据，证明了MeCP2的S与染色质重塑因子BRG1和DNA甲基转移酶DNMT1相关的功能作用，提示MeCP2在MOR基因调控过程中可能参与染色质重塑。我们的结论是，MOR基因的表达在不同的脑区是表观遗传编程的，MeCP2在DNA甲基化和染色质重塑MOR启动子的过程中辅助表观遗传程序。
The pharmacological action of morphine as a pain medication is mediated primarily through the μ-opioid receptor (MOR). With few exceptions, MOR is expressed in brain regions where opioid actions take place. The basis for this unique spatial expression of MOR remains undetermined. Recently, we reported that DNA methylation of the MOR promoter plays an important role in regulating MOR in P19 cells. In this study, we show that the differential expression of MOR in microdissected mouse brain regions coincides with DNA methylation and histone modifications. MOR expression could be induced by a demethylating agent or a histone deacetylase inhibitor in MOR-negative cells, suggesting that the MOR gene can be silenced under epigenetic control. Increases in the in vivo interaction of methyl-CpG-binding protein 2 (MeCP2) were observed in the cerebellum, in which the MOR promoter was hypermethylated and MOR expression was the lowest among all brain regions tested. MeCP2 is associated closely with Rett syndrome, a neurodevelopmental disorder. We also established novel evidence for a functional role for MeCP2’s association with the chromatin-remodelling factor Brg1 and DNA methyltransferase Dnmt1, suggesting a possible role for MeCP2 in chromatin remodelling during MOR gene regulation. We conclude that MOR gene expression is epigenetically programmed in various brain regions and that MeCP2 assists the epigenetic program during DNA methylation and chromatin remodelling of the MOR promoter.