Genome-wide redistribution of MeCP2 in dorsal root ganglia after peripheral nerve injury.
Genome-wide redistribution of MeCP2 in dorsal root ganglia after peripheral nerve injury.
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DOI：
10.1186/s13072-016-0073-5
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发表时间：
2016
影响因子：
3.9
通讯作者：
Ajit SK
中科院分区：
文献类型：
--
作者：
Manners MT;Ertel A;Tian Y;Ajit SK
甲基CpG结合蛋白2(MeCP2)是一种与甲基化胞嘧啶具有亲和力的蛋白质，对神经元的发育和功能至关重要。MeCP2通过激活、抑制和染色质重塑来调节基因表达。MeCP2的突变会导致Rett综合征，这些患者表现出伤害性感受受损。我们观察到周围神经损伤后小鼠背根神经节(DRG)中MeCP2的表达增加。MeCP2增加的功能含义在很大程度上尚不清楚。为了确定MeCP2在DRG中的结合区域以及神经损伤后的变化，在备用神经损伤(SNI)后4周进行了MeCP2染色质免疫沉淀和测序(CHIP-SEQ)。虽然在SNI模型和假对照中，基因组上的结合位点数量保持相似，但SNI诱导了MeCP2的重新分布到转录相关区域。为了确定MeCP2的差异结合如何影响DRG中的基因表达，我们研究了MMU-miR-126，这是一个在SNI模型中丰富MeCP2结合的微RNA座位。神经损伤后，与miR-126位点甲基化结合的MeCP2增强抑制了miR-126的表达，这不是通过miR-126位点甲基化模式的改变来实现的。与对照组相比，miR-126的下调导致其两个靶基因Dnmt1和Vegfa在Neuro 2A细胞和SNI模型中上调。与野生型小鼠相比，这些靶基因在MeCP2缺失型小鼠中显著下调，表明MeCP2在激活Dnmt1和Vegfa表达方面具有调节作用。鞘内注射miR-126不足以逆转神经损伤诱导的机械和温度超敏反应，但可降低DRG中Dnmt1和Vegfa的表达。我们的研究表明，MeCP2的调节作用在于全球再分布的变化可以导致DRG中基因表达的直接和间接调节。因此，MeCP2全基因组结合的变化为更好地理解表观遗传调控诱导的神经损伤潜在的分子变化提供了分子基础。本文的在线版本(doi：10.1186/s13072-0160073-5)包含补充材料，授权用户可以使用。
Methyl-CpG-binding protein 2 (MeCP2), a protein with affinity for methylated cytosines, is crucial for neuronal development and function. MeCP2 regulates gene expression through activation, repression and chromatin remodeling. Mutations in MeCP2 cause Rett syndrome, and these patients display impaired nociception. We observed an increase in MeCP2 expression in mouse dorsal root ganglia (DRG) after peripheral nerve injury. The functional implication of increased MeCP2 is largely unknown. To identify regions of the genome bound by MeCP2 in the DRG and the changes induced by nerve injury, a chromatin immunoprecipitation of MeCP2 followed by sequencing (ChIP-seq) was performed 4 weeks after spared nerve injury (SNI). While the number of binding sites across the genome remained similar in the SNI model and sham control, SNI induced the redistribution of MeCP2 to transcriptionally relevant regions. To determine how differential binding of MeCP2 can affect gene expression in the DRG, we investigated mmu-miR-126, a microRNA locus that had enriched MeCP2 binding in the SNI model. Enriched MeCP2 binding to miR-126 locus after nerve injury repressed miR-126 expression, and this was not mediated by alterations in methylation pattern at the miR-126 locus. Downregulation of miR-126 resulted in the upregulation of its two target genes Dnmt1 and Vegfa in Neuro 2A cells and in SNI model compared to control. These target genes were significantly downregulated in Mecp2-null mice compared to wild-type littermates, indicating a regulatory role for MeCP2 in activating Dnmt1 and Vegfa expression. Intrathecal delivery of miR-126 was not sufficient to reverse nerve injury-induced mechanical and thermal hypersensitivity, but decreased Dnmt1 and Vegfa expression in the DRG. Our study shows a regulatory role for MeCP2 in that changes in global redistribution can result in direct and indirect modulation of gene expression in the DRG. Alterations in genome-wide binding of MeCP2 therefore provide a molecular basis for a better understanding of epigenetic regulation-induced molecular changes underlying nerve injury. The online version of this article (doi:10.1186/s13072-016-0073-5) contains supplementary material, which is available to authorized users.