Developing neurons undergo a progression of morphological and gene expression changes as they transition from neuronal progenitors to mature neurons. Here we used RNA-seq and H3K4me3 and H3K27me3 ChIP-seq to analyze how chromatin modifications control gene expression in a specific type of CNS neuron: the mouse cerebellar granule cell (GC). We found that in proliferating GC progenitors (GCPs), H3K4me3/H3K27me3 bivalency is common at neuronal genes and undergoes dynamic changes that correlate with gene expression during migration and circuit formation. Expressing a fluorescent sensor for bivalent domains revealed subnuclear bivalent foci in proliferating GCPs. Inhibiting H3K27 methyltransferases EZH1 and EZH2 in vitro and in organotypic cerebellar slices dramatically altered the expression of bivalent genes, induced the down-regulation of migration-related genes and up-regulation of synaptic genes, inhibited glial-guided migration, and accelerated terminal differentiation. Thus, histone bivalency is required to regulate the timing of the progression from progenitor cells to mature neurons.

中文翻译：

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组蛋白二价调节小脑颗粒细胞发育的时间

发育中的神经元从神经祖细胞转变为成熟神经元时会经历一系列形态和基因表达变化。在这里，我们使用 RNA-seq 以及 H3K4me3 和 H3K27me3 ChIP-seq 来分析染色质修饰如何控制特定类型 CNS 神经元（小鼠小脑颗粒细胞 (GC)）中的基因表达。我们发现，在增殖的GC祖细胞（GCP）中，H3K4me3/H3K27me3二价在神经元基因中很常见，并且在迁移和电路形成过程中经历与基因表达相关的动态变化。表达二价结构域的荧光传感器揭示了增殖 GCP 中的亚核二价焦点。在体外和器官型小脑切片中抑制 H3K27 甲基转移酶 EZH1 和 EZH2 可显着改变二价基因的表达，诱导迁移相关基因的下调和突触基因的上调，抑制神经胶质引导的迁移并加速终末分化。因此，需要组蛋白二价来调节从祖细胞到成熟神经元的进展时间。