Histone methylation mediated by NSD1 is required for the establishment and maintenance of neuronal identities
Yue Zheng,
Chen Zhao,
Qiulin Song,
Lichao Xu,
Bo Zhang,
Guangda Hu,
Xiangfei Kong,
Shaowen Li,
Xiang Li,
Yin Shen,
Lenan Zhuang,
Min Wu,
Ying Liu,
Yan Zhou
Affiliations
Yue Zheng
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
Chen Zhao
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
Qiulin Song
Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan 430071, China; Eye Center, Wuhan University Renmin Hospital, Wuhan 430071, China
Lichao Xu
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
Bo Zhang
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
Guangda Hu
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
Xiangfei Kong
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
Shaowen Li
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
Xiang Li
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
Yin Shen
Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan 430071, China; Eye Center, Wuhan University Renmin Hospital, Wuhan 430071, China
Lenan Zhuang
Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
Min Wu
Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan 430071, China; College of Life Sciences, Taikang Center for Life and Medical Sciences of Wuhan University, Wuhan 430071, China; Corresponding author
Ying Liu
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; Corresponding author
Yan Zhou
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; Corresponding author
Summary: 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.
