Neuronal Histone Methyltransferase EZH2 Regulates Neuronal Morphogenesis, Synaptic Plasticity, and Cognitive Behavior in Mice
Mei Zhang1,5 · Yong Zhang2 · Qian Xu2 · Joshua Crawford3 · Cheng Qian1 · Guo‑Hua Wang4 · Jiang Qian4 · Xin‑Zhong Dong2 · Mikhail V. Pletnikov3 · Chang‑Mei Liu1,6 · Feng‑Quan Zhou1,2,71 Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore 21205, USA
2 The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore 21205, USA
3 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore 21205, USA
4 Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore 21205, USA
5 School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
6 State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China
7 Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
Abstract
The histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)-mediated trimethylation of histone H3 lysine 27 (H3K27me3) regulates neural stem cell proliferation and fate specificity through silencing different gene sets in the central nervous system. Here, we explored the function of EZH2 in early post-mitotic neurons by generating a neuron-specific Ezh2 conditional knockout mouse line. The results showed that a lack of neuronal EZH2 led to delayed neuronal migration, more complex dendritic arborization, and increased dendritic spine density. Transcriptome analysis revealed that neuronal EZH2-regulated genes are related to neuronal morphogenesis. In particular, the gene encoding p21-activated kinase 3 (Pak3) was identified as a target gene suppressed by EZH2 and H3K27me3, and expression of the dominant negative Pak3 reversed Ezh2 knockout-induced higher dendritic spine density. Finally, the lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice. Our results demonstrated that neuronal EZH2 acts to control multiple steps of neuronal morphogenesis during development, and has long-lasting effects on cognitive function in adult mice.
Keywords
Neural development; Dendritic branching; Dendritic spine; Cognitive function; Epigenetics; Histone methylation; EZH2
