CHD8 haploinsufficiency results in autistic-like phenotypes in mice

  • Nature volume 537, pages 675679 (29 September 2016)
  • doi:10.1038/nature19357
  • Download Citation


Autism spectrum disorder (ASD) comprises a range of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as by restricted and repetitive behaviours1. ASD has a strong genetic component with high heritability. Exome sequencing analysis has recently identified many de novo mutations in a variety of genes in individuals with ASD2,3, with CHD8, a gene encoding a chromatin remodeller, being most frequently affected4,5,6,7,8. Whether CHD8 mutations are causative for ASD and how they might establish ASD traits have remained unknown. Here we show that mice heterozygous for Chd8 mutations manifest ASD-like behavioural characteristics including increased anxiety, repetitive behaviour, and altered social behaviour. CHD8 haploinsufficiency did not result in prominent changes in the expression of a few specific genes but instead gave rise to small but global changes in gene expression in the mouse brain, reminiscent of those in the brains of patients with ASD. Gene set enrichment analysis revealed that neurodevelopment was delayed in the mutant mouse embryos. Furthermore, reduced expression of CHD8 was associated with abnormal activation of RE-1 silencing transcription factor (REST), which suppresses the transcription of many neuronal genes. REST activation was also observed in the brains of humans with ASD, and CHD8 was found to interact physically with REST in the mouse brain. Our results are thus consistent with the notion that CHD8 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis probably resulting from a delay in neurodevelopment.

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Data deposits

Sequencing data have been deposited in the DDBJ sequence read archive under accession number DRA003116.


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We thank Y. Kita, K. Tsunematsu, K. Maehara, S. Hirata, M. Kato, Y. Nakajo, T. Akasaka, M. Tanaka, Y. Yamada and K. Takeda for technical assistance; as well as K. Tamada for discussion. Computed tomography was supported by the Center for Advanced Instrumental and Educational Support, Faculty of Agriculture, Kyushu University. This study was supported in part by KAKENHI and by a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Author information


  1. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan

    • Yuta Katayama
    • , Masaaki Nishiyama
    • , Atsuki Kawamura
    •  & Keiichi I. Nakayama
  2. Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan

    • Hirotaka Shoji
    •  & Tsuyoshi Miyakawa
  3. Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan

    • Yasuyuki Ohkawa
  4. Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan

    • Tetsuya Sato
    •  & Mikita Suyama
  5. RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan

    • Toru Takumi


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M.N. and A.K. assisted with animal preparation and molecular biology experiments. H.S. and T.M. conducted behavioural studies. Y.O., T.S. and M.S. performed sequencing and data analysis. Y.K. performed all other experiments and data analysis. T.T. interpreted results. K.I.N. coordinated the study and wrote the manuscript. All authors discussed the data and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Masaaki Nishiyama or Keiichi I. Nakayama.

Reviewer Information Nature thanks E. Eichler, C. Powell and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figure 1, which show the original uncropped western or southern blots for Figures 1a, 4e and Extended Data Figures 1c, d, f, 2e, f, 6a, and 10f, h. The black frames denote how the gels were cropped for the final figure. It also contains a Supplementary Discussion and additional references.

Excel files

  1. 1.

    Supplementary Table 1

    This file contains the source data for behavioural tests.

  2. 2.

    Supplementary Table 2

    This file contains statistical analysis of behavioural data.

  3. 3.

    Supplementary Table 3

    This file contains results (MACS P value, expression level, fold change, and P value) for total genes of ChIP-seq or RNA-seq analysis used in this study.

  4. 4.

    Supplementary Table 4

    This file contains gene symbols of original gene sets and complete results of GSEA reported in the manuscript.


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