DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling
DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling
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DOI：
10.1242/dev.01912
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发表时间：
2005-08-01
期刊：
影响因子：
4.6
通讯作者：
Sun, YE
中科院分区：
文献类型：
--
作者：
Fan, GP;Martinowich, K;Sun, YE
DNA甲基化是一种主要的表观遗传因素，据推测它可调节细胞谱系分化。我们在此报道，在神经祖细胞（NPCs）中条件性基因缺失维持性DNA甲基转移酶I（Dnmt1）会导致DNA低甲基化以及早熟的星形胶质细胞分化。在Dnmt1（-/-）神经祖细胞中，星形胶质细胞标记基因以及编码胶质细胞生成的JAK - STAT通路关键组分的基因的发育调控去甲基化过程加速。通过染色质重塑过程，JAK - STAT通路中基因的去甲基化导致STATs的激活增强，进而触发星形胶质细胞分化。我们的研究表明，在神经发生期间，DNA甲基化不仅抑制星形胶质细胞标记基因，还抑制对JAK - STAT信号传导至关重要的基因。因此，这两组基因的去甲基化以及随后STAT活性的升高是控制星形胶质细胞分化的时间和程度的关键机制。
DNA methylation is a major epigenetic factor that has been postulated to regulate cell lineage differentiation. We report here that conditional gene deletion of the maintenance DNA methyltransferase I (Dnmt1) in neural progenitor cells (NPCs) results in DNA hypomethylation and precocious astroglial differentiation. The developmentally regulated demethylation of astrocyte marker genes as well as genes encoding the crucial components of the gliogenic JAK-STAT pathway is accelerated in Dnmt1(-/-) NPCs. Through a chromatin remodeling process, demethylation of genes in the JAK-STAT pathway leads to an enhanced activation of STATs, which in turn triggers astrocyte differentiation. Our study suggests that during the neurogenic period, DNA methylation inhibits not only astroglial marker genes but also genes that are essential for JAK-STAT signaling. Thus, demethylation of these two groups of genes and subsequent elevation of STAT activity are key mechanisms that control the timing and magnitude of astroglial differentiation.