Developmental Epigenetic Modification Regulates Stochastic Expression of Clustered Protocadherin Genes, Generating Single Neuron Diversity

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• 作者：Shunsuke Toyoda¹ ; ² ; Masahumi Kawaguchi¹ ; Toshihiro Kobayashi³ ; ⁴ ; Etsuko Tarusawa² ; ⁵ ; Tomoko Toyama¹ ; Masaki Okano⁶ ; Masaaki Oda⁶ ; Hiromitsu Nakauchi³ ; ⁴ ; Yumiko Yoshimura⁵ ; ⁷ ; Makoto Sanbo² ; ⁸ ; Masumi Hirabayashi² ; ⁷ ; ⁸ ; Teruyoshi Hirayama¹ ; ² ; Takahiro Hirabayashi¹ ; ² ; Takeshi Yagi¹ ; ² ; ^{yagi@fbs.osaka-u.ac.jp" class="auth_mail}
• 刊名：Neuron
• 出版年：2 April, 2014
• 年：2014
• 卷：82
• 期：1
• 页码：94-108
• 全文大小：3446 K

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Summary

In the brain, enormous numbers of neurons have functional individuality and distinct circuit specificities. Clustered Protocadherins (Pcdhs), diversified cell-surface proteins, are stochastically expressed by alternative promoter choice and affect dendritic arborization in individual neurons. Here we found that the Pcdh promoters are differentially methylated by the de novo DNA methyltransferase Dnmt3b during early embryogenesis. To determine this methylation鈥檚 role in neurons, we produced chimeric mice from Dnmt3b-deficient induced pluripotent stem cells (iPSCs). Single-cell expression analysis revealed that individual Dnmt3b-deficient Purkinje cells expressed increased numbers of Pcdh isoforms; in聽vivo, they exhibited abnormal dendritic arborization. These results indicate that DNA methylation by Dnmt3b at聽early embryonic stages regulates the probability of expression for the stochastically expressed Pcdh isoforms. They also suggest a mechanism for a rare聽human recessive disease, the ICF (Immunodeficiency, Centromere instability, and Facial anomalies) syndrome, which is caused by Dnmt3b mutations.