Kohyama Jun, Kojima Takuro, Takatsuka Eriko, Yamashita Toru, Namiki Jun, Hsieh Jenny, Gage Fred H, Namihira Masakazu, Okano Hideyuki, Sawamoto Kazunobu, Nakashima Kinichi
Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara 630-0101, Japan.
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):18012-7. doi: 10.1073/pnas.0808417105. Epub 2008 Nov 12.
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.
神经干细胞/祖细胞（NSCs/NPCs）可分化产生神经元、星形胶质细胞和少突胶质细胞。目前已经明确，包括DNA甲基化在内的细胞内表观遗传修饰，与细胞因子信号传导等细胞外信号协同作用，通过定义细胞类型特异性基因表达，深度参与NSCs/NPCs的命运决定。然而，目前仍不清楚分化的神经细胞如何通过抑制其他谱系特有的细胞特性来维持其特定属性。在之前的研究中，我们发现甲基化CpG结合蛋白转录抑制因子（MBDs）主要在中枢神经系统的神经元中表达，通过结合其靶基因的高度甲基化区域来抑制星形胶质细胞特异性基因表达。在此，我们报告，不表达MBDs的少突胶质细胞可通过激活JAK/STAT信号通路，在体外（细胞因子刺激）和体内（缺血性损伤）转分化为星形胶质细胞。这些发现表明，神经细胞的分化可塑性受细胞内在表观遗传机制与周围细胞外信号协同调控。
