Phf21b imprints the spatiotemporal epigenetic switch essential for neural stem cell differentiation
Phf21b imprints the spatiotemporal epigenetic switch essential for neural stem cell differentiation
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DOI：
10.1101/gad.333906.119
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发表时间：
2020-09-01
影响因子：
10.5
通讯作者：
Tiwari, Vijay K.
中科院分区：
文献类型：
--
作者：
Basu, Amitava;Mestres, Ivan;Tiwari, Vijay K.
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）从增殖分裂到分化分裂以产生神经元的转变。尽管取得了进展，时空调节这种增殖分化开关在神经发生和上游表观遗传触发仍然知之甚少。在这里，我们报告了一种皮质特异性PHD指蛋白，Phf 21 b，它在皮质发育的神经发生阶段高度表达，并在神经干细胞开始分化时被诱导。体内Phf21b的耗尽抑制神经元分化，因为缺乏Phf21b的皮质祖细胞保留在增殖区并经历更快的细胞周期。从机制上讲，Phf21b凭借其对单甲基化H3K4的高亲和力靶向细胞周期促进基因的调控区域。随后，Phf21b募集赖氨酸特异性脱甲基酶Lsd 1和组蛋白脱乙酰酶Hdac 2，分别导致同时去除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症和精神发育迟滞有关。总之，这些发现建立了一个精确定时的时空表达的Phf21b如何创建一个表观遗传程序，触发神经干细胞分化在皮层发育。
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 neuro genesis 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.