MeCP2 deficiency downregulates specific nuclear proteins that could be partially recovered by valproic acid in vitro
MeCP2 deficiency downregulates specific nuclear proteins that could be partially recovered by valproic acid in vitro
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DOI：
10.4161/epi.5.1.10630
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发表时间：
2010-01-01
期刊：
影响因子：
3.7
通讯作者：
Gak, Eva
中科院分区：
文献类型：
--
作者：
Vecsler, Manuela;Simon, Amos J.;Gak, Eva
MeCP 2是Rett综合征和包括自闭症在内的相关表型的主要致病因子，是通过转录和染色质重塑机制起作用的双面核调节剂。本研究调查了几种核蛋白的表达及其对MeCP 2剂量和Rett致病R306 C突变的依赖性。为此，我们开发了由siRNA诱导的MeCP 2缺陷的体外模型和表达R306 C突变的细胞。使用通过特定测定验证的扩展抗体微阵列，揭示MeCP 2剂量与特定核蛋白谱相关，包括SWI/SNF复合物的BRM/SNF 2组分、PRMT 1甲基转移酶和HDAC 2。此外，当将MeCP 2敲低系统暴露于治疗浓度的丙戊酸（VPAPA）（一种已知的HDAC抑制剂）时，我们观察到MeCP 2表达水平的部分恢复。暴露于VPAPA也增加了BRM以及BDNF的水平，BDNF是MeCP 2介导的途径中的重要辅因子。我们的研究结果提供了额外的证据，不同的机制MeCP 2功能作为转录抑制因子和激活剂的特定基因。由于最近已经证明，出生后恢复MeCP 2缺陷可能会逆转Rett综合征小鼠模型中的神经缺陷，我们建议研究HDAC抑制剂在MeCP 2缺陷小鼠模型中的恢复作用。
MeCP2, the major causative factor of Rett syndrome and related phenotypes including autism, is a two-face nuclear modulator acting via transcriptional and chromatin remodeling mechanisms. This study investigated the expression of several nuclear proteins and their dependence on MeCP2 dose and presence of the Rett causative R306C mutation. To this end, we developed in vitro models representing MeCP2 deficiency induced by siRNAs, and cells expressing the R306C mutation. Using an extended antibody microarray validated by specific assays, revealed that MeCP2 dose was correlated with specific nuclear proteins profiles including the BRM/SNF2 component of SWI/SNF complex, PRMT1 methyl transferase and HDAC2. Furthermore, while exposing the MeCP2 knock-down system to therapeutic concentrations of valproic acid (VPAPA), a known HDACs inhibitor, we observed a partial restoration of MeCP2 expression levels. Exposure to VPAPA also increased the levels of BRM, as well as of BDNF, an important co-factor in MeCP2-mediated pathway. Our findings provide additional evidence of diverse mechanisms of MeCP2 function as transcriptional repressor and activator of specific genes. As it has been recently demonstrated that post-natal restoration of MeCP2 deficiency may reverse neurological defects in a mouse model of Rett syndrome, we suggest to study the restorative effect of HDAC inhibitors in MeCP2-deficient mouse model.