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首页> 外文期刊>Journal of Molecular Biology >Gene-specific methylation control of H3K9 and H3K36 on neurotrophic BDNF versus astroglial GFAP genes by KDM4A/C regulates neural stem cell differentiation
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Gene-specific methylation control of H3K9 and H3K36 on neurotrophic BDNF versus astroglial GFAP genes by KDM4A/C regulates neural stem cell differentiation

机译：通过KDM4A / C控制神经营养性BDNF与星形胶质GFAP基因对H3K9和H3K36的基因特异性甲基化调节神经干细胞分化

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摘要

Neural stem cell (NSC) state and fate depend on spatially and temporally synchronized transcriptional and epigenetic regulation of the expression of extrinsic signaling factors and intrinsic cell-specific genes, but the functional roles for chromatin-modifying enzymes in neural differentiation remain poorly understood. Here we show that the histone demethylases KDM4A (JMJD2A) and KDM4C (JMJD2C) are essential for proper differentiation of NSCs in vitro and in vivo. KDM4A/C were required for neuronal differentiation, survival and expression of the neurotrophic signaling factor BDNF in association with promoter H3K9 demethylation and RNA polymerase II recruitment. Unexpectedly, KDM4A/C were essential for selective H3K36 demethylation and loss of RNA polymerase II recruitment in transcribed regions of the astrocyte-characteristic gene GFAP, thereby in parallel repressing astrocytic differentiation by control of elongation. We propose that gene- and lysine-specific KDM4A/C-mediated control of histone methylation and thereby regulation of intrinsic factors and signaling factors such as BDNF provide a novel control mechanism of lineage decision.
机译：神经干细胞（NSC）的状态和命运取决于外在信号转导因子和内在细胞特异性基因表达的时空同步转录和表观遗传调控，但染色质修饰酶在神经分化中的功能作用仍然知之甚少。在这里，我们显示组蛋白脱甲基酶KDM4A（JMJD2A）和KDM4C（JMJD2C）对于在体外和体内对NSC的正确分化至关重要。与启动子H3K9去甲基化和RNA聚合酶II募集有关，神经元分化，神经营养信号因子BDNF的存活和表达需要KDM4A / C。出乎意料的是，KDM4A / C对于星形胶质特征基因GFAP转录区域中的选择性H3K36脱甲基化和RNA聚合酶II募集的丢失是必不可少的，从而通过控制伸长来并行抑制星形胶质细胞分化。我们建议，基因和赖氨酸特异性的KDM4A / C介导的组蛋白甲基化控制，从而调节内在因素和信号因子（如BDNF）提供了谱系决定的新型控制机制。

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