Methyl‐CpG binding proteins are involved in restricting differentiation plasticity in neurons
Methyl‐CpG binding proteins are involved in restricting differentiation plasticity in neurons
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DOI：
10.1002/jnr.21001
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发表时间：
2006-10
影响因子：
4.2
通讯作者：
Hiroki Setoguchi;M. Namihira;J. Kohyama;Hirotsugu Asano;Tsukasa Sanosaka;K. Nakashima
中科院分区：
文献类型：
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作者：
Hiroki Setoguchi;M. Namihira;J. Kohyama;Hirotsugu Asano;Tsukasa Sanosaka;K. Nakashima
神经元和星形胶质细胞由共同的神经前体产生，但神经发生先于星形胶质细胞发生，星形胶质细胞发生通常在发育的后期开始。我们以前曾报道过，随着妊娠的进行，星形胶质细胞特异性标志物胶质细胞酸性蛋白（GFAP）基因启动子中STAT 3结合位点内的一个特定胞嘧啶残基在神经上皮细胞中发生去甲基化。这种去甲基化与星形胶质细胞分化的发生密切相关，表明细胞类型特异性基因启动子的DNA甲基化变化控制着发育中大脑从神经发生到星形胶质细胞发生的转变。在这里，我们表明，妊娠晚期神经上皮细胞已经失去了GFAP启动子内STAT 3结合位点的甲基化，仍然可以产生神经元，并且这些神经元不响应STAT 3激活细胞因子来表达GFAP。作为转录抑制因子家族的成员，甲基化-CpG结合蛋白（MBD），包括MeCP 2，主要在神经元中表达，并且异位MeCP 2表达抑制神经上皮细胞的星形胶质细胞分化。此外，我们发现，GFAP基因的外显子1保持高甲基化，即使在神经上皮细胞在发育后期阶段，并从这样的神经上皮细胞分化的神经元。我们进一步证明，MeCP 2实际上结合到神经元中GFAP基因的高度甲基化的外显子1。这些结果表明，区域特异性DNA甲基化和MBD在神经元分化可塑性的调节中起重要作用。© 2006 Wiley利斯公司
Neurons and astrocytes are generated from common neural precursors, yet neurogenesis precedes astrocytogenesis, which normally commences at later stages of development. We have previously reported that a particular cytosine residue within a STAT3‐binding site in the astrocyte‐specific marker glial fibrillary acidic protein (GFAP) gene promoter becomes demethylated in neuroepithelial cells as gestation proceeds. This demethylation correlates tightly with the onset of astrocyte differentiation, suggesting that a change in DNA methylation at cell‐type‐specific gene promoters controls the switch from neurogenesis to astrocytogenesis in the developing brain. Here, we show that late‐gestation neuroepithelial cells, which have already lost the methylation in the STAT3‐binding site within the GFAP promoter, can still give rise to neurons and that these neurons do not respond to a STAT3‐activating cytokine to express GFAP. Members of a transcriptional repressor family, the methylated‐CpG binding proteins (MBDs), including MeCP2, are predominantly expressed in neurons, and ectopic MeCP2 expression inhibited astrocyte differentiation of neuroepithelial cells. Moreover, we found that exon 1 of the GFAP gene remains hypermethylated even in neuroepithelial cells at a late developmental stage and in neurons differentiated from such neuroepithelial cells. We further demonstrate that MeCP2 actually binds to the highly methylated exon 1 of the GFAP gene in neurons. These results suggest that region‐specific DNA methylation and MBDs play an important role in the regulation of differentiation plasticity in neurons. © 2006 Wiley‐Liss, Inc.