Zheng Yue, Zhao Chen, Song Qiulin, Xu Lichao, Zhang Bo, Hu Guangda, Kong Xiangfei, Li Shaowen, Li Xiang, Shen Yin, Zhuang Lenan, Wu Min, Liu Ying, Zhou Yan
Department of Neurosurgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan 430071, China.
Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan 430071, China; Eye Center, Wuhan University Renmin Hospital, Wuhan 430071, China.
Cell Rep. 2023 Dec 26;42(12):113496. doi: 10.1016/j.celrep.2023.113496. Epub 2023 Nov 22.
Appropriate histone modifications emerge as essential cell fate regulators of neuronal identities across neocortical areas and layers. Here we showed that NSD1, the methyltransferase for di-methylated lysine 36 of histone H3 (H3K36me2), controls both area and layer identities of the neocortex. Nsd1-ablated neocortex showed an area shift of all four primary functional regions and aberrant wiring of cortico-thalamic-cortical projections. Nsd1 conditional knockout mice displayed defects in spatial memory, motor learning, and coordination, resembling patients with the Sotos syndrome carrying NSD1 mutations. On Nsd1 loss, superficial-layer pyramidal neurons (PNs) progressively mis-expressed markers for deep-layer PNs, and PNs remained immature both morphologically and electrophysiologically. Loss of Nsd1 in postmitotic PNs causes genome-wide loss of H3K36me2 and re-distribution of DNA methylation, which accounts for diminished expression of neocortical layer specifiers but ectopic expression of non-neural genes. Together, H3K36me2 mediated by NSD1 is required for the establishment and maintenance of region- and layer-specific neocortical identities.
适当的组蛋白修饰成为跨新皮质区域和层的神经元身份的重要细胞命运调节因子。在这里，我们表明，组蛋白H3赖氨酸36二甲基化（H3K36me2）的甲基转移酶NSD1控制新皮质的区域和层身份。Nsd1缺失的新皮质显示所有四个主要功能区域的区域转移以及皮质-丘脑-皮质投射的异常布线。Nsd1条件性敲除小鼠在空间记忆、运动学习和协调方面表现出缺陷，类似于携带NSD1突变的索托斯综合征患者。在Nsd1缺失时，浅层锥体神经元（PNs）逐渐错误表达深层PNs的标记物，并且PNs在形态和电生理上都保持不成熟。有丝分裂后PNs中Nsd1的缺失导致全基因组H3K36me2的丧失和DNA甲基化的重新分布，这解释了新皮质层特异性标记物表达的减少但非神经基因的异位表达。总之，NSD1介导的H3K36me2是区域和层特异性新皮质身份建立和维持所必需的。
