Autism Spectrum Disorders (ASD) associated rare loss of function genetic variant in SUV39H2; a putative role of H3K9 methylation dynamics in ASD pathogenesis

最近的证据证明了组蛋白修饰酶在自闭症谱系障碍（ASD）中的潜在作用。由组蛋白甲基转移酶遗传变异引起的异常组蛋白H3赖氨酸9 （H3K9）二甲基化是已知的神经发育和行为异常的原因。然而，缺乏对ASD中H3K9甲基化动力学的系统研究。在这里，我们使用靶向新一代测序技术对ASD患者和健康对照中涉及H3K9甲基化的组蛋白甲基转移酶和去甲基化酶的9个基因进行了重新测序。我们在SUV39H2中发现了一种新的罕见变异（A211S），预计它是有害的。该变异在体外表现出组蛋白甲基转移酶活性的强烈降低。Suv39h2-KO小鼠在学习需要复杂行为适应的任务时表现出多动症和行为灵活性降低，这与ASD有关。suv39h2缺陷引起胚胎脑中原钙粘蛋白β (Pcdhb)簇基因亚群的表达升高，这是由于基因启动子处H3K9三甲基化（me3）的缺失。本研究为SUV39H2在ASD中的作用提供了直接证据，并提示SUV39H2功能障碍的分子级联导致H3K9me3缺乏，随后在早期神经发育过程中过早地升高Pcdhb簇基因的表达。

Recent evidence has documented the potential roles of histone-modifying enzymes in autism spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) di-methylation resulting from genetic variants in histone methyltransferases is known for neurodevelopmental and behavioral anomalies. However, a systematic examination of H3K9 methylation dynamics in ASD is lacking. Here we resequenced nine genes for histone methyltransferases and demethylases involved in H3K9 methylation in individuals with ASD and healthy controls using targeted next-generation sequencing. We identified a novel rare variant (A211S) in the SUV39H2, which was predicted to be deleterious. The variant showed strongly reduced histone methyltransferase activity in vitro. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which are relevant for ASD. The Suv39h2-deficit evoked an elevated expression of a subset of protocadherin β (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. The present study provides direct evidence for the role of SUV39H2 in ASD, and suggests a molecular cascade of SUV39H2 dysfunction leading to H3K9me3 deficiency followed by an untimely, elevated expression of Pcdhb cluster genes during early neurodevelopment.