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.

中文翻译：

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JMJD3和UTX确定人类神经祖细胞的保真度和谱系规格。

神经发生是一个高度协调的过程，需要从多能状态过渡到神经状态，并涉及神经祖细胞（NPC）和神经元/神经胶质亚型。然而，关于命运决定的确切表观遗传机制仍然知之甚少。在这里，我们删除了人类胚胎干细胞（hESCs）中的KDM6s（JMJD3和/或UTX），H3K27me3脱甲基酶，并表明它们的删除并不妨碍hESCs产生NPC。但是，缺乏KDM6的NPC表现出较差的增殖，并且无法分化为神经元和神经胶质。从机理上讲，发现JMJD3和UTX都富含hNPC中神经发育必不可少的基因位点，而KDM6损伤导致H3K27me3积累并阻断了这些基因的DNA可达性。有趣的是 尽管H3K27me3积累，神经元特异性染色质重塑BAF（nBAF）的强制表达可挽救KDM6缺陷型NPC中的神经元/神经胶质缺陷。我们的发现揭示了在指定NPC和神经元/神经胶质中KDM6的差异需求，并强调了人类发展模型中命运决定中各个表观遗传调控因子的贡献。