Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain
Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain
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DOI：
10.1073/pnas.0808417105
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发表时间：
2008-11-18
影响因子：
11.1
通讯作者：
Nakashima, Kinichi
中科院分区：
文献类型：
--
作者：
Kohyama, Jun;Kojima, Takuro;Nakashima, Kinichi
神经干/祖细胞（NSC/NPC）产生神经元、星形胶质细胞和少突胶质细胞。已经变得明显的是，包括DNA甲基化在内的细胞内表观遗传修饰，与细胞外线索如细胞因子信号传导相一致，通过定义细胞类型特异性基因表达而深深参与NSC/NPC的命运特化。然而，目前尚不清楚分化的神经细胞如何通过抑制其他谱系的细胞特性来保持其特定属性。在以前的工作中，我们已经表明，甲基-CpG结合蛋白转录抑制因子（MBDs），这是主要在中枢神经系统的神经元中表达，抑制星形胶质细胞特异性基因的表达，结合高度甲基化的区域，其目标基因。在这里，我们报告说，少突胶质细胞，不表达MBDs，可以转分化成星形胶质细胞在体外（细胞因子刺激）和体内（缺血性损伤）通过激活JAK/STAT信号通路。这些研究结果表明，神经细胞的分化可塑性是由细胞内在的表观遗传机制与周围细胞外在的线索合作。
Neural stem/progenitor cells (NSCs/NPCs) give rise to neurons, astrocytes, and oligodendrocytes. It has become apparent that intracellular epigenetic modification including DNA methylation, in concert with extracellular cues such as cytokine signaling, is deeply involved in fate specification of NSCs/NPCs by defining cell-type specific gene expression. However, it is still unclear how differentiated neural cells retain their specific attributes by repressing cellular properties characteristic of other lineages. In previous work we have shown that methyl-CpG binding protein transcriptional repressors (MBDs), which are expressed predominantly in neurons in the central nervous system, inhibit astrocyte-specific gene expression by binding to highly methylated regions of their target genes. Here we report that oligodendrocytes, which do not express MBDs, can transdifferentiate into astrocytes both in vitro (cytokine stimulation) and in vivo (ischemic injury) through the activation of the JAK/STAT signaling pathway. These findings suggest that differentiation plasticity in neural cells is regulated by cell-intrinsic epigenetic mechanisms in collaboration with ambient cell-extrinsic cues.