A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain
A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain
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DOI：
10.1038/s41380-021-01199-7
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发表时间：
2021-07-15
影响因子：
11
通讯作者：
Yoshikawa, Takeo
中科院分区：
文献类型：
--
作者：
Balan, Shabeesh;Iwayama, Yoshimi;Yoshikawa, Takeo
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。组蛋白甲基转移酶基因变异导致的组蛋白 H3 赖氨酸 9 (H3K9) 二甲基化异常会导致神经发育和行为异常。然而，缺乏对 ASD 中 H3K9 甲基化动态的系统检查。在这里，我们使用靶向下一代测序对 ASD 个体和健康对照个体中参与 H3K9 甲基化的 9 个组蛋白甲基转移酶和去甲基化酶基因进行了重新测序。我们在 SUV39H2 中发现了一种新的罕见变体 (A211S)，预计该变体是有害的。该变体在体外表现出强烈降低的组蛋白甲基转移酶活性。计算机分析表明，该变体破坏了疏水核心的稳定性，并变构地影响了酶活性。 Suv39h2-KO 小鼠在学习需要复杂行为适应的任务时表现出过度活跃和行为灵活性降低，这与 ASD 相关。 Suv39h2 缺陷引起胚胎脑中原钙粘蛋白β (Pcdhb) 簇基因子集的表达升高，这是由于基因启动子处 H3K9 三甲基化 (me3) 的缺失。 Suv39h2 缺陷小鼠的小脑中 H3K9me3 的减少持续到成年阶段。相应地，在 ASD 个体死后脑样本中观察到 SUV39H1 和 SUV39H2 表达降低，强调了 H3K9me3 缺陷在 ASD 病因学中的作用。本研究为 SUV39H2 在 ASD 中的作用提供了直接证据，并表明 SUV39H2 功能障碍的分子级联导致 H3K9me3 缺陷，随后在早期神经发育过程中 Pcdhb 簇基因的表达不合时宜地升高。
Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) dimethylation 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. In silico analysis showed that the variant destabilizes the hydrophobic core and allosterically affects the enzyme activity. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which is relevant for ASD. The Suv39h2 deficit evoked an elevated expression of a subset of protocadherin beta (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. Reduced H3K9me3 persisted in the cerebellum of Suv39h2-deficient mice to an adult stage. Congruently, reduced expression of SUV39H1 and SUV39H2 in the postmortem brain samples of ASD individuals was observed, underscoring the role of H3K9me3 deficiency in ASD etiology. 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.