Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard Medical School, Boston, MA 02115, USA.
Neuron. 2018 Jun 6;98(5):945-962.e8. doi: 10.1016/j.neuron.2018.04.033. Epub 2018 May 17.
The epigenetic landscape is dynamically remodeled during neurogenesis. However, it is not understood how chromatin modifications in neural stem cells instruct the formation of complex structures in the brain. We report that the histone methyltransferase PRDM16 is required in radial glia to regulate lineage-autonomous and stage-specific gene expression programs that control number and position of upper layer cortical projection neurons. PRDM16 regulates the epigenetic state of transcriptional enhancers to activate genes involved in intermediate progenitor cell production and repress genes involved in cell migration. The histone methyltransferase domain of PRDM16 is necessary in radial glia to promote cortical neuron migration through transcriptional silencing. We show that repression of the gene encoding the E3 ubiquitin ligase PDZRN3 by PRDM16 determines the position of upper layer neurons. These findings provide insights into how epigenetic control of transcriptional enhancers in radial glial determines the organization of the mammalian cerebral cortex.
表观基因组景观在神经发生过程中动态重塑。然而，尚不清楚神经干细胞中的染色质修饰如何指导大脑中复杂结构的形成。我们报告称，组蛋白甲基转移酶 PRDM16 在放射状胶质细胞中是必需的，以调节谱系自主和阶段特异性基因表达程序，控制上皮质层投射神经元的数量和位置。PRDM16 调节转录增强子的表观遗传状态，以激活参与中间祖细胞产生的基因，并抑制参与细胞迁移的基因。PRDM16 的组蛋白甲基转移酶结构域在放射状胶质细胞中是必需的，可通过转录沉默促进皮质神经元迁移。我们表明，PRDM16 对 E3 泛素连接酶 PDZRN3 编码基因的抑制作用决定了上皮质层神经元的位置。这些发现为我们提供了深入了解转录增强子在放射状胶质细胞中的表观遗传控制如何决定哺乳动物大脑皮层的组织方式。
