Xu Lichao, Zheng Yue, Li Xuejing, Wang Andi, Huo Dawei, Li Qinglan, Wang Shikang, Luo Zhiyuan, Liu Ying, Xu Fuqiang, Wu Xudong, Wu Min, Zhou Yan
College of Life Sciences, Department of Neurosurgery, Zhongnan Hospital of Wuhan University; Frontier Science Center for Immunology and Metabolism, and Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430071, China.
Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Qixiangtai Road 22, Tianjin 300070, China.
Sci Adv. 2021 Jan 1;7(1). doi: 10.1126/sciadv.aba1180. Print 2021 Jan.
Proper formation of area identities of the cerebral cortex is crucial for cognitive functions and social behaviors of the brain. It remains largely unknown whether epigenetic mechanisms, including histone methylation, regulate cortical arealization. Here, we removed SETD2, the methyltransferase for histone 3 lysine-36 trimethylation (H3K36me3), in the developing dorsal forebrain in mice and showed that is required for proper cortical arealization and the formation of cortico-thalamo-cortical circuits. Moreover, conditional knockout mice exhibit defects in social interaction, motor learning, and spatial memory, reminiscent of patients with the Sotos-like syndrome bearing mutations. SETD2 maintains the expression of clustered protocadherin () genes in an H3K36me3 methyltransferase-dependent manner. Aberrant cortical arealization was recapitulated in heterozygous mice. Together, our study emphasizes epigenetic mechanisms underlying cortical arealization and pathogenesis of the Sotos-like syndrome.
大脑皮质区域身份的正确形成对于大脑的认知功能和社会行为至关重要。包括组蛋白甲基化在内的表观遗传机制是否调节皮质区域化在很大程度上仍不清楚。在这里，我们在小鼠发育中的背侧前脑中去除了组蛋白3赖氨酸-36三甲基化（H3K36me3）的甲基转移酶SETD2，结果表明其对于正确的皮质区域化和皮质-丘脑-皮质回路的形成是必需的。此外，条件性敲除小鼠在社交互动、运动学习和空间记忆方面表现出缺陷，这让人联想到患有类似索托斯综合征且携带突变的患者。SETD2以H3K36me3甲基转移酶依赖的方式维持成簇原钙黏蛋白（）基因的表达。在杂合小鼠中再现了异常的皮质区域化。总之，我们的研究强调了皮质区域化和类似索托斯综合征发病机制的表观遗传机制。
