Chromatin Mechanisms of Neuronal Fate Decisions

Fate specification and differentiation of Neural Stem Cells (NSCs) depend on the transcriptional silencing of alternative developmental programs. This process is determined by the cell type-specific regulation of transcriptional enhancers via chromatin modifications. However, how specific subsets of enhancers are silenced in NSCs and how this process controls neurogenesis and neuronal differentiation remain elusive. Here, we aim to discover the mechanisms of enhancer silencing by histone modifications and their role in neuronal fate decisions. It is known that the histone H3 lysine 9 (H3K9) methyltransferase PRDM16 is specifically expressed in NSCs of the mammalian cerebral cortex. PRDM16 regulates transcriptional enhancers and controls neurogenesis, neuronal fate specification, and migration in the developing mouse cortex. In this project, we combined a series of molecular, cellular, biochemical, and genomics approaches to elucidate the mechanism by which PRDM16 and its interacting partners regulate enhancers in the developing mouse cortex.

神经干细胞（Neural Stem Cells, NSCs）的命运特化与分化，依赖于对替代性发育程序的转录沉默。该过程由细胞类型特异性的染色质修饰调控转录增强子所介导。然而，神经干细胞中特定亚群的增强子如何被沉默，以及该过程如何调控神经发生与神经元分化，目前仍尚不明确。本研究旨在揭示组蛋白修饰介导的增强子沉默机制，及其在神经元命运决定中的作用。已知组蛋白H3赖氨酸9（H3K9）甲基转移酶PRDM16在哺乳动物大脑皮层的神经干细胞中特异性表达。PRDM16可调控转录增强子，并在发育中小鼠大脑皮层中调控神经发生、神经元命运特化与细胞迁移。本项目结合一系列分子、细胞、生化及基因组学研究手段，旨在阐明PRDM16及其互作伙伴调控发育中小鼠大脑皮层内增强子的具体分子机制。