Fujita Yuki, Masuda Koji, Bando Masashige, Nakato Ryuichiro, Katou Yuki, Tanaka Takashi, Nakayama Masahiro, Takao Keizo, Miyakawa Tsuyoshi, Tanaka Tatsunori, Ago Yukio, Hashimoto Hitoshi, Shirahige Katsuhiko, Yamashita Toshihide
Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
J Exp Med. 2017 May 1;214(5):1431-1452. doi: 10.1084/jem.20161517. Epub 2017 Apr 13.
Abnormal epigenetic regulation can cause the nervous system to develop abnormally. Here, we sought to understand the mechanism by which this occurs by investigating the protein complex cohesin, which is considered to regulate gene expression and, when defective, is associated with higher-level brain dysfunction and the developmental disorder Cornelia de Lange syndrome (CdLS). We generated conditional -knockout mice and observed greater dendritic complexity and larger numbers of immature synapses in the cerebral cortex of mice. mice also exhibited more anxiety-related behavior, which is a symptom of CdLS. Further, a gene ontology analysis after RNA-sequencing suggested the enrichment of immune processes, particularly the response to interferons, in the mice. Indeed, fewer synapses formed in their cortical neurons, and this phenotype was rescued by STAT1 knockdown. Thus, low levels of cohesin expression in the developing brain lead to changes in gene expression that in turn lead to a specific and abnormal neuronal and behavioral phenotype.
异常的表观遗传调控会导致神经系统发育异常。在此，我们试图通过研究蛋白质复合物黏连蛋白来了解其发生机制，黏连蛋白被认为可调节基因表达，且当其功能缺陷时，与更高级别的脑功能障碍及发育障碍科妮莉亚·德朗热综合征（CdLS）相关。我们构建了条件性敲除小鼠，并观察到小鼠大脑皮层中树突复杂性增加以及未成熟突触数量增多。这些小鼠还表现出更多与焦虑相关的行为，这是CdLS的一种症状。此外，RNA测序后的基因本体分析表明，这些小鼠中免疫过程富集，尤其是对干扰素的反应。实际上，它们的皮质神经元中形成的突触较少，而这种表型可通过STAT1基因敲低得到挽救。因此，发育中的大脑中黏连蛋白表达水平较低会导致基因表达发生变化，进而导致特定的异常神经元和行为表型。
