Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Neuron. 2019 Feb 6;101(3):472-485.e7. doi: 10.1016/j.neuron.2018.12.010. Epub 2019 Jan 9.
Minimal sets of transcription factors can directly reprogram somatic cells into neurons. However, epigenetic remodeling during neuronal reprogramming has not been well reconciled with transcriptional regulation. Here we show that NeuroD1 achieves direct neuronal conversion from mouse microglia both in vitro and in vivo. Exogenous NeuroD1 initially occupies closed chromatin regions associated with bivalent trimethylation of histone H3 at lysine 4 (H3K4me3) and H3K27me3 marks in microglia to induce neuronal gene expression. These regions are resolved to a monovalent H3K4me3 mark at later stages of reprogramming to establish the neuronal identity. Furthermore, the transcriptional repressors Scrt1 and Meis2 are induced as NeuroD1 target genes, resulting in a decrease in the expression of microglial genes. In parallel, the microglial epigenetic signature in promoter and enhancer regions is erased. These findings reveal NeuroD1 pioneering activity accompanied by global epigenetic remodeling for two sequential events: onset of neuronal property acquisition and loss of the microglial identity during reprogramming.
少量的转录因子可以直接将体细胞重编程为神经元。然而，神经元重编程过程中的表观遗传重塑尚未与转录调控很好地协调。在这里，我们展示了 NeuroD1 可以在体外和体内将小鼠小胶质细胞直接转化为神经元。外源性的 NeuroD1 最初占据与小胶质细胞中组蛋白 H3 赖氨酸 4 上的二价三甲基化（H3K4me3）和 H3K27me3 标记相关的封闭染色质区域，以诱导神经元基因表达。在重编程的后期，这些区域被解析为单价 H3K4me3 标记，以建立神经元的身份。此外，转录抑制因子 Scrt1 和 Meis2 作为 NeuroD1 的靶基因被诱导，导致小胶质细胞基因的表达减少。同时，启动子和增强子区域的小胶质细胞表观遗传特征被消除。这些发现揭示了 NeuroD1 的开拓性活动伴随着全局表观遗传重塑，这是两个连续事件的结果：获得神经元特性的开始和重编程过程中小胶质细胞身份的丧失。
