A research team led by Professor Masaaki Nishiyama from the Institute for Frontier Science Initiative, and the Graduate School of Medical Sciences at Kanazawa University; Assistant Professor Atsuki Kawamura from the same faculty (at the time of the research, currently a postdoctoral researcher at the University of California, Berkeley); and Professor Keizo Takao from the Graduate School of Medicine, University of Toyama, demonstrated using a mouse model that duplication (i.e., overexpression) of the Chd8 gene (*1), which is associated with autism spectrum disorder (hereafter referred to as ASD), results in neurodevelopmental abnormalities such as growth retardation, hyperactivity, and microcephaly.
The CHD8 gene is known to have one of the highest mutation frequencies among genes associated with ASD, and numerous studies have investigated the effects of its loss of function (deficiency). In contrast, increased copy number (duplication) (*2) of chromosomal regions that include the CHD8 locus has been repeatedly identified in patients with developmental disorders. However, how CHD8 duplication affects brain development and contributes to the pathogenesis of developmental disorders has remained poorly understood.
To replicate the increased copy number of the CHD8 gene, the research team developed a novel mouse model that overexpresses CHD8 and conducted a detailed analysis of its effects. As a result, they found that Chd8 -duplicated mice exhibit delayed brain development from the embryonic stage and develop microcephaly. These mice showed abnormal differentiation of neural progenitor cells and a marked reduction in the production of deep-layer cortical neurons in the cerebral cortex. Furthermore, transcriptomic analysis revealed that excessive CHD8 expression led to aberrant binding of CHD8 to enhancer regions (*3) of genes involved in neurogenesis, resulting in transcriptional dysregulation.
Behavioral analysis of the Chd8 -duplicated mice revealed phenotypes such as hyperactivity and reduced anxiety-like behavior—traits commonly observed in patients with developmental disorders involving CHD8 gene duplication. Notably, some of these behavioral abnormalities were alleviated by administration of risperidone (*4), an antipsychotic medication used in the treatment of ASD, indicating the potential for therapeutic intervention in CHD8 duplication-related behavioral symptoms. This research is expected to contribute to a deeper understanding of the developmental mechanisms underlying such disorders and to the development of new treatment strategies.
The research results were published in the online edition of the British scientific journal Nature Communications on May 26, 2025 at 6:00 p.m. (JST).
Figure 1: Chromatin remodeling by CHD8
Chromosomes (chromatin) are highly compacted structures stored within the nucleus, where DNA is wrapped around proteins called histones to form nucleosomes. Gene expression is regulated through the relaxation and condensation of chromatin. CHD8 possesses chromatin remodeling activity, altering chromatin structure to control the activation (ON) and repression (OFF) of gene transcription.
Figure 2: Developmental disorder model caused by CHD8 Duplication-Induced Developmental Disorders and Its Therapeutic Potential
The research team generated a novel mouse model with Chd8 duplication and conducted comprehensive analyses at the molecular, cellular, and organismal levels. These findings are expected to advance our understanding of the pathophysiology of developmental disorders and contribute to the development of new therapeutic approaches.
【Glossary】
*1：CHD8
CHD8 stands for chromodomain helicase DNA-binding protein 8. It belongs to a class of proteins known as chromatin remodeling factors, which utilize intracellular energy to alter chromatin structure and regulate gene expression levels.
*2: Copy number increase (duplication)
This condition involves an increased number of copies of a specific gene or its surrounding chromosomal region. Normally, each cell contains two copies of a gene—one inherited from each parent. However, when duplication occurs, the number of copies can increase to three or more.
This leads to elevated expression levels (i.e., increased protein production) of the affected gene, which can disrupt cellular balance and interfere with normal developmental processes.
*3: Enhancer region
A specific regulatory region on DNA that strongly influences the expression (activation or repression) of genes located either nearby or at a distance
*4: Risperidone
A type of antipsychotic drug that alleviates behavioral abnormalities such as hyperactivity, aggression, and anxiety by modulating the activity of neurotransmitters—specifically dopamine and serotonin—in the brain. It is also approved for the treatment of ASD-related symptoms. In this study, risperidone was shown to improve certain behavioral abnormalities in Chd8-duplicated mice, suggesting its potential as a therapeutic intervention.
Click here to see the press release【Japanese only】
Journal: Nature Communications
Researcher's Information：Masaaki Nishiyama
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