PDF(Pubmed)
Abstract：
Quiescence, a hallmark of adult neural stem cells (NSCs), is required for maintaining the NSC pool to support life-long continuous neurogenesis in the adult dentate gyrus (DG). Whether long-lasting epigenetic modifications maintain NSC quiescence over the long term in the adult DG is not well-understood. Here we show that mice with haploinsufficiency of Setd1a, a schizophrenia risk gene encoding a histone H3K4 methyltransferase, develop an enlarged DG with more dentate granule cells after young adulthood. Deletion of Setd1a specifically in quiescent NSCs in the adult DG promotes their activation and neurogenesis, which is countered by inhibition of the histone demethylase LSD1. Mechanistically, RNA-sequencing and CUT & RUN analyses of cultured quiescent adult NSCs reveal Setd1a deletion-induced transcriptional changes and many Setd1a targets, among which down-regulation of Bhlhe40 promotes quiescent NSC activation in the adult DG in vivo. Together, our study reveals a Setd1a-dependent epigenetic mechanism that sustains NSC quiescence in the adult DG.
摘要：
静止，成人神经干细胞（NSC）的标志，需要维护NSC池以支持成年齿状回（DG）中的终生连续神经发生。长期持续的表观遗传修饰是否在成年DG中长期维持NSC静止尚不清楚。在这里，我们显示了Sett1a单倍体不足的小鼠，编码组蛋白H3K4甲基转移酶的精神分裂症风险基因，成年后发展出一个扩大的DG，有更多的齿状颗粒细胞。在成年DG的静止NSC中特异性缺失Sett1a促进其激活和神经发生,这通过抑制组蛋白去甲基酶LSD1来抵消。机械上,对培养的静止成年神经干细胞的RNA测序和CUT&RUN分析揭示了Sett1a缺失诱导的转录变化和许多Sett1a靶标。其中Bhlhe40的下调促进体内成年DG中静止的NSC激活。一起,我们的研究揭示了Sett1a依赖的表观遗传机制，该机制维持成年DG的NSC静止。
