Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus.
Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus.
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DOI：
10.1093/hmg/ddp181
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发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Zoghbi HY
中科院分区：
文献类型：
--
作者：
Ben-Shachar S;Chahrour M;Thaller C;Shaw CA;Zoghbi HY
一组产后神经发育障碍被统称为MeCP2障碍，是由编码甲基 - CpG结合蛋白2（MECP2）的基因异常引起的。MeCP2功能缺失导致瑞特综合征（RTT），而该基因拷贝数增加则导致MECP2重复或三倍体综合征。MeCP2作为一种转录抑制因子，然而在MeCP2障碍小鼠模型的下丘脑中观察到的基因表达变化表明，MeCP2也可以上调基因表达，因为大多数基因在MeCP2缺失时下调，在其存在时上调。为了确定MeCP2的这种双重作用是否延伸到下丘脑以外，我们分别研究了Mecp2缺失和MECP2转基因小鼠小脑中的基因表达模式，这两种小鼠分别模拟RTT和MECP2重复综合征。我们发现异常的MeCP2剂量会导致小脑中数百个基因的表达发生改变。大多数基因在MECP2转基因小鼠中上调，在Mecp2缺失小鼠中下调，这与MeCP2作为一种既能增加又能降低基因表达的调节剂的作用是一致的。有趣的是，小脑中许多发生改变的基因，特别是那些因MeCP2存在而增加、因MeCP2缺失而减少的基因，在下丘脑中也有类似的改变。我们的数据表明，MeCP2的获得或缺失都会导致多个脑区的基因表达变化，并且其中一些变化是全局性的。进一步描绘MeCP2靶基因在整个大脑中的表达模式可能会识别出更易于操作的基因子集，从而可用于调节一些疾病表型。
A group of post-natal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased copy number of the gene causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however the gene expression changes observed in the hypothalamus of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression, given that the majority of genes are downregulated upon loss of MeCP2 and upregulated in its presence. To determine if this dual role of MeCP2 extends beyond the hypothalamus, we studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-Tg mice, modeling RTT and MECP2 duplication syndrome, respectively. We found that abnormal MeCP2 dosage causes alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MeCP2 as a modulator that can both increase and decrease gene expression. Interestingly, many of the genes altered in the cerebellum, particularly those increased by the presence of MeCP2 and decreased in its absence, were similarly altered in the hypothalamus. Our data suggest that either gain or loss of MeCP2 results in gene expression changes in multiple brain regions and that some of these changes are global. Further delineation of the expression pattern of MeCP2 target genes throughout the brain might identify subsets of genes that are more amenable to manipulation, and can thus be used to modulate some of the disease phenotypes.
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影响因子：
3.3
作者：
Carter, Alan N.;Cole, Clare L.;Shervington, Amal A.
通讯作者：
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