Cerebral cortical development in mammals involves a highly complex and organized set of events including the transition of neural stem and progenitor cells (NSCs) from proliferative to differentiative divisions to generate neurons. Despite progress, the spatiotemporal regulation of this proliferation-differentiation switch during neurogenesis and the upstream epigenetic triggers remain poorly known. Here we report a cortex-specific PHD finger protein, Phf21b, which is highly expressed in the neurogenic phase of cortical development and gets induced as NSCs begin to differentiate. Depletion of Phf21b in vivo inhibited neuronal differentiation as cortical progenitors lacking Phf21b were retained in the proliferative zones and underwent faster cell cycles. Mechanistically, Phf21b targets the regulatory regions of cell cycle promoting genes by virtue of its high affinity for monomethylated H3K4. Subsequently, Phf21b recruits the lysine-specific demethylase Lsd1 and histone deacetylase Hdac2, resulting in the simultaneous removal of monomethylation from H3K4 and acetylation from H3K27, respectively. Intriguingly, mutations in the Phf21b locus associate with depression and mental retardation in humans. Taken together, these findings establish how a precisely timed spatiotemporal expression of Phf21b creates an epigenetic program that triggers neural stem cell differentiation during cortical development.

中文翻译：

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Phf21b印记了神经干细胞分化必不可少的时空表观遗传开关。

哺乳动物的大脑皮层发育涉及一系列高度复杂和有组织的事件，包括神经干细胞和祖细胞（NSC）从增生分裂向分化分化转变为神经元的过程。尽管取得了进展，但在神经发生和上游表观遗传触发过程中这种增殖-分化开关的时空调节仍然知之甚少。在这里，我们报道了一种皮质特异的PHD手指蛋白Phf21b，该蛋白在皮质发育的神经发生期高表达，并随着NSCs的分化而被诱导。体内缺乏Phf21b会抑制神经元分化，因为缺乏Phf21b的皮质祖细胞保留在增生区中，并经历了更快的细胞周期。机械上，Phf21b凭借对单甲基化H3K4的高亲和力而靶向于细胞周期促进基因的调控区。随后，Phf21b募集赖氨酸特异性脱甲基酶Lsd1和组蛋白脱乙酰基酶Hdac2，从而分别同时去除了H3K4的单甲基化和H3K27的乙酰化。有趣的是，Phf21b基因座的突变与人类的抑郁和智力低下有关。综上所述，这些发现确定了Phf21b的精确时空表达如何创建表观遗传程序，从而在皮质发育过程中触发神经干细胞分化。导致同时从H3K4中除去一甲基化和从H3K27中被乙酰化。有趣的是，Phf21b基因座的突变与人类的抑郁和智力低下有关。综上所述，这些发现确定了Phf21b的精确时空表达如何创建表观遗传程序，从而在皮质发育过程中触发神经干细胞分化。导致同时从H3K4中除去一甲基化和从H3K27中被乙酰化。有趣的是，Phf21b基因座的突变与人类的抑郁和智力低下有关。综上所述，这些发现确定了Phf21b的精确时空表达如何创建表观遗传程序，从而在皮质发育过程中触发神经干细胞分化。