JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells
JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells
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JMJD3 和 UTX 确定人类神经祖细胞的保真度和谱系规范
DOI：
10.1038/s41467-019-14028-x
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发表时间：
2020-01-20
影响因子：
16.6
通讯作者：
Pan, Guangjin
中科院分区：
文献类型：
--
作者：
Shan, Yongli;Zhang, Yanqi;Pan, Guangjin
神经发生是一个高度协调的过程，需要从多能状态到神经状态的转变，涉及神经祖细胞（npc）和神经元/胶质亚型。然而，命运决定背后的精确表观遗传机制仍然知之甚少。在这里，我们在人胚胎干细胞（hESCs）中删除了H3K27me3去甲基化酶KDM6s (JMJD3和/或UTX)，并表明它们的删除不会阻碍hESCs产生NPC。然而，缺乏kdm6的npc表现为增殖不良，不能分化为神经元和胶质细胞。从机制上讲，在hNPCs中发现JMJD3和UTX都富集于神经发育所必需的基因位点，KDM6损伤导致H3K27me3积累并阻断这些基因的DNA可及性。有趣的是，尽管H3K27me3积累，但强迫表达神经元特异性染色质重塑BAF （nBAF）可以挽救kdm6缺陷的npc的神经元/胶质缺陷。我们的研究结果揭示了kdm6在指定npc和神经元/胶质细胞方面的差异需求，并强调了个体表观遗传调节剂在人类发育模型中命运决定中的贡献。
Neurogenesis, a highly orchestrated process, entails the transition from a pluripotent to neural state and involves neural progenitor cells (NPCs) and neuronal/glial subtypes. However, the precise epigenetic mechanisms underlying fate decision remain poorly understood. Here, we delete KDM6s (JMJD3 and/or UTX), the H3K27me3 demethylases, in human embryonic stem cells (hESCs) and show that their deletion does not impede NPC generation from hESCs. However, KDM6-deficient NPCs exhibit poor proliferation and a failure to differentiate into neurons and glia. Mechanistically, both JMJD3 and UTX are found to be enriched in gene loci essential for neural development in hNPCs, and KDM6 impairment leads to H3K27me3 accumulation and blockade of DNA accessibility at these genes. Interestingly, forced expression of neuron-specific chromatin remodelling BAF (nBAF) rescues the neuron/glia defect in KDM6-deficient NPCs despite H3K27me3 accumulation. Our findings uncover the differential requirement of KDM6s in specifying NPCs and neurons/glia and highlight the contribution of individual epigenetic regulators in fate decisions in a human development model.