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

自闭症谱系障碍 (ASD) 与 SUV39H2 中罕见的功能丧失遗传变异相关；

基本信息

批准号：
19K08084
负责人：
SHABEESH BALAN
金额：
$ 2.75万
依托单位：
Institute of Physical and Chemical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2019
资助国家：
日本
起止时间：
2019-04-01 至 2021-03-31
项目状态：
已结题

项目摘要

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.

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H3赖氨酸9(H3K9)由组蛋白甲基转移酶基因变异引起的异常甲基化是神经发育和行为异常的常见原因。然而，缺乏对ASD中H3K9甲基化动态的系统检查。在这里，我们使用定向下一代测序法对ASD患者和健康对照组中涉及H3K9甲基化的组蛋白甲基转移酶和去甲基酶的九个基因进行了重新测序。我们在SUV39H2中发现了一个新的罕见变异(A211S)，据预测它是有害的。该变异体在体外表现出明显的组蛋白甲基转移酶活性降低。Suv39h2-KO小鼠在学习需要复杂行为适应的任务时表现出多动，行为灵活性降低，这与ASD相关。Suv39h2缺失引起胚胎脑中原钙粘附素β(Pcdhb)簇基因子集表达上调，这可归因于基因启动子上H3K9三甲基化(ME3)的丢失。本研究为SUV39H2在ASD中的作用提供了直接证据，并提示SUV39H2功能障碍导致H3K9me3缺陷的分子级联反应，随后在神经发育的早期，Pcdhb簇基因过早地高表达。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic determinants of epigenetic modifications contributing to the ASD pathogenesis’

导致 ASD 发病机制的表观遗传修饰的遗传决定因素

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Shimamoto-Mitsuyama Chie;Ohnishi Tetsuo;Balan Shabeesh;Ohba Hisako;Watanabe Akiko;Maekawa Motoko;Hisano Yasuko;Iwayama Yoshimi;Owada Yuji;Yoshikawa Takeo;Shabeesh Balan
通讯作者：
Shabeesh Balan

Evaluation of the role of fatty acid-binding protein 7 in controlling schizophrenia-relevant phenotypes using newly established knockout mice

使用新建立的基因敲除小鼠评估脂肪酸结合蛋白7在控制精神分裂症相关表型中的作用

DOI：
10.1016/j.schres.2019.02.002
发表时间：
2019
期刊：
Schizophrenia Research
影响因子：
4.5
作者：
Shimamoto-Mitsuyama Chie;Ohnishi Tetsuo;Balan Shabeesh;Ohba Hisako;Watanabe Akiko;Maekawa Motoko;Hisano Yasuko;Iwayama Yoshimi;Owada Yuji;Yoshikawa Takeo
通讯作者：
Yoshikawa Takeo

Investigation of betaine as a novel psychotherapeutic for schizophrenia.

甜菜碱作为精神分裂症新型心理治疗药物的研究。

DOI：
10.1016/j.ebiom.2019.05.062
发表时间：
2019
期刊：
EBioMedicine
影响因子：
11.1
作者：
Ohnishi T;Balan S;Toyoshima M;Maekawa M;Ohba H;Watanabe A;Iwayama Y;Fujita Y;Tan Y;Hisano Y;Shimamoto-Mitsuyama C;Nozaki Y;Esaki K;Nagaoka A;Matsumoto J;Hino M;Mataga N;Hayashi-Takagi A;Hashimoto K;Kunii Y;Kakita A;Yabe H;Yoshikawa T
通讯作者：
Yoshikawa T

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