Abnormal neocortex arealization and Sotos-like syndrome-associated behavior in Setd2 mutant mice

Epigenetic regulation of gene expression through histone modifications like methylation of various lysine residues are essential for embryonic development. Here we removed SETD2, a methyltransferase for histone 3 lysine 36 trimethylation (H3K36me3), in the developing dorsal forebrain in mice and show it is required for proper area patterning (arealization) of the neocortex and the formation of thalamo-cortico-thalamic circuits by maintaining the expression of clustered protocadherin (Pcdh) genes in an H3K36me3 methyltransferase-dependent manner. Moreover, the Setd2 mutant mice exhibit defects in social interaction, motor endurance and spatial memory, reminiscent of patients with the Sotos-like syndrome bearing SETD2 mutations. Cortex mRNA profiles of E13.5 control and Emx1-Cre;Setd2 fl/fl mice were generated by deep sequencing, in triplicate, using Illumina NovaSeq 6000.通过组蛋白修饰（如多种赖氨酸残基的甲基化）实现的基因表观遗传调控，对胚胎发育至关重要。本研究在小鼠发育中的背侧前脑内敲除了介导组蛋白3赖氨酸36三甲基化（H3K36me3）的甲基转移酶SETD2，发现其可通过以H3K36me3甲基转移酶依赖性方式维持成簇原钙粘蛋白（Pcdh）基因的表达，对新皮质的正常脑区模式建成（arealization）以及丘脑-皮质-丘脑环路的形成具有必需作用。此外，Setd2突变小鼠表现出社交互动缺陷、运动耐力减退与空间记忆障碍，其表型与携带SETD2突变的类Sotos综合征患者高度相似。本研究采用Illumina NovaSeq 6000平台，对3份生物学重复样本的E13.5（胚胎发育第13.5天）对照组及Emx1-Cre;Setd2 fl/fl条件性敲除小鼠的皮质mRNA进行了深度测序，获取了其转录组表达谱。