Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome
Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome
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DOI：
10.1038/ng1491
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发表时间：
2005-01-01
期刊：
影响因子：
30.8
通讯作者：
Kohwi-Shigematsu, T
中科院分区：
文献类型：
--
作者：
Horike, S;Cai, ST;Kohwi-Shigematsu, T
MECP 2的突变与Rett综合征有关，Rett综合征是一种X连锁神经发育障碍。为了鉴定Mecp 2靶向的基因，我们对小鼠大脑中的100个体内Mecp 2结合位点进行了测序。几个序列映射到6号染色体上的印记基因簇，包括Dlx 5和Dlx 6，其转录在Mecp 2缺失小鼠的大脑中比野生型小鼠的转录高出大约两倍。母系表达基因DLX 5在Rett综合征患者的淋巴母细胞中表现出印记缺失。由于Dlx 5调节合成γ-氨基丁酸（GABA）的酶的产生，因此Dlx 5印记的丧失可能会改变Rett综合征患者的GABA能神经元活性。在小鼠脑中，Dlx 5印记是松弛的，但Mecp 2介导的沉默染色质结构存在于野生型小鼠脑中的Dlx 5-Dlx 6位点，而不是Mecp 2-null小鼠。Mecp 2将组蛋白去乙酰化酶1定位于Dlx 5-Dlx 6位点上一个清晰的、类似于1-kb的区域，并促进该位点上Lys 9的抑制性组蛋白甲基化。染色质免疫沉淀结合环分析表明，Mecp 2介导沉默的染色质衍生的11 kb染色质环在Dlx 5-Dlx 6位点。这个环在Mecp 2缺失小鼠的脑染色质中不存在，并且Dlx 5-Dlx 6与远距离序列相互作用，形成不同的活性染色质相关环。这些结果表明，沉默染色质环的形成是Mecp 2基因调控的一种新机制。
Mutations in MECP2 are associated with Rett syndrome, an X-linked neurodevelopmental disorder. To identify genes targeted by Mecp2, we sequenced 100 in vivo Mecp2-binding sites in mouse brain. Several sequences mapped to an imprinted gene cluster on chromosome 6, including Dlx5 and Dlx6, whose transcription was roughly two times greater in brains of Mecp2-null mice compared with those of wild-type mice. The maternally expressed gene DLX5 showed a loss of imprinting in lymphoblastoid cells from individuals with Rett syndrome. Because Dlx5 regulates production of enzymes that synthesize gamma-aminobutyric acid (GABA), loss of imprinting of Dlx5 may alter GABAergic neuron activity in individuals with Rett syndrome. In mouse brain, Dlx5 imprinting was relaxed, yet Mecp2-mediated silent-chromatin structure existed at the Dlx5-Dlx6 locus in brains of wild-type, but not Mecp2-null, mice. Mecp2 targeted histone deacetylase 1 to a sharply defined, similar to1-kb region at the Dlx5-Dlx6 locus and promoted repressive histone methylation at Lys9 at this site. Chromatin immunoprecipitation-combined loop assays showed that Mecp2 mediated the silent chromatin-derived 11-kb chromatin loop at the Dlx5-Dlx6 locus. This loop was absent in chromatin of brains of Mecp2-null mice, and Dlx5-Dlx6 interacted with far distant sequences, forming distinct active chromatin-associated loops. These results show that formation of a silent-chromatin loop is a new mechanism underlying gene regulation by Mecp2.