Silencing Trisomy 21 with XIST in Neural Stem Cells Promotes Neuronal Differentiation
Silencing Trisomy 21 with XIST in Neural Stem Cells Promotes Neuronal Differentiation
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DOI：
10.1016/j.devcel.2019.12.015
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发表时间：
2020-02-10
影响因子：
11.8
通讯作者：
Lawrence, Jeanne Bentley
中科院分区：
文献类型：
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作者：
Czerminski, Jan Tomasz;Lawrence, Jeanne Bentley
XIST对三体常染色体的剂量补偿能力提供了独特的实验机会和潜在的变革性治疗前景。然而，目前认为XIST需要围绕多能性的自然环境来启动染色体沉默。在这里，我们证明在分化的神经细胞中诱导的XIST RNA可以触发唐氏综合征患者来源的细胞中21号染色体的全染色体沉默。使用这种严格控制的系统揭示了三体神经干细胞向神经元分化的缺陷，可以通过在神经发生的不同阶段诱导XIST来纠正。单细胞转录组学和其他分析强烈暗示由于21三体导致Notch信号升高，从而促进神经干细胞循环，延迟末梢分化。这些发现对于阐明细胞在发育过程中的表观遗传可塑性，理解人类21三体如何影响唐氏综合征神经生物学，以及XIST（一种独特的非编码RNA）的翻译潜力具有重要意义。
The ability of XIST to dosage compensate a trisomic autosome presents unique experimental opportunities and potentially transformative therapeutic prospects. However, it is currently thought that XIST requires the natural context surrounding pluripotency to initiate chromosome silencing. Here, we demonstrate that XIST RNA induced in differentiated neural cells can trigger chromosome-wide silencing of chromosome 21 in Down syndrome patient-derived cells. Use of this tightly controlled system revealed a deficiency in differentiation of trisomic neural stem cells to neurons, correctible by inducing XIST at different stages of neurogenesis. Single-cell transcriptomics and other analyses strongly implicate elevated Notch signaling due to trisomy 21, thereby promoting neural stem cell cycling that delays terminal differentiation. These findings have significance for illuminating the epigenetic plasticity of cells during development, the understanding of how human trisomy 21 effects Down syndrome neurobiology, and the translational potential of XIST, a unique non-coding RNA.