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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

Molecular Psychiatry volume 26, pages 7550–7559 (2021)Cite this article

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Abstract

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 β (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.

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Fig. 1: ASD-specific rare variants in the genes involved in H3K9 methylation and its functional assessment.
Fig. 2: Evaluating the LoF imparted by the ASD-specific SUV39H2 A211S variant by in vitro and in silico methods.
Fig. 3: Behavioral evaluation of Suv39h2-KO mice.
Fig. 4: Suv39h2 deficiency in the developing brain results in loss of H3K9me3 and changes in the regulation of gene expression.

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Acknowledgements

We acknowledge RIKEN Center for Computational Science for the supercomputing resources at the Hokusai BigWaterfall and Bioinformatics Analysis Environment Service (BAYES) on RIKEN Cloud. We are grateful to the Support Unit for Bio-Material Analysis and Animal Resources Development, Research Resources Division, RIKEN Center for Brain Science, for sequencing service and animal care. We also thank Drs. Yasuhide Iwata, Katsuaki Suzuki, Kenji J. Tsuchiya, Shu Takagai, and Norio Mori from Hamamatsu University School of Medicine, and the Asperger Society Japan for their kind help for recruiting and collecting human samples, Dr. Akihiro Ito for kindly providing 293 T cells, and Drs. Shigehiro Kuraku and Mitsutaka Kadota from Laboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics Research, for their helpful suggestions for ChIP-PCR.

Funding

This work was supported by Grant-in-Aid for Scientific Research (C) (KAKENHI) by Japan Society for the Promotion of Science (JSPS) under Grant number (19K08084 to S.B.), Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Number (JP18H05435 to T.Y.), Core Research for Evolutionary Science and Technology (CREST) from the Japan Agency for Medical Research and Development (AMED) (12101571 to T.Y. and Y.S.), and RIKEN internal research funds (to T.Y. and Y.S.), and a grant of the Deutsche Forschungsgemeinschaft (JE 252/7-4 to A.J.). The funding agencies had no role in study design, data collection, and analysis, decision to publish, or preparation of the paper.

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Authors and Affiliations

  1. Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan

    Shabeesh Balan, Yoshimi Iwayama, Tetsuo Ohnishi, Yasuko Hisano, Tomoko Toyota, Akiko Watanabe, Hisako Ohba, Motoko Maekawa, Manabu Toyoshima & Takeo Yoshikawa

  2. Neuroscience Research Laboratory, Institute of Mental Health and Neurosciences (IMHANS), Kozhikode, Kerala, India

    Shabeesh Balan

  3. Department of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    Tetsuo Ohnishi

  4. Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan

    Mikiko Fukuda, Atsuko Shirai, Ayumi Yamada, Kaoru Kotoshiba & Yoichi Shinkai

  5. Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, Stuttgart, Germany

    Sara Weirich, Maren Kirstin Schuhmacher & Albert Jeltsch

  6. Laboratory for Structural Bioinformatics, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan

    Kalarickal Vijayan Dileep & Kam Y. J. Zhang

  7. Phenovance Research and Technology LLC, Kashiwa, Chiba, Japan

    Toshihiro Endo

  8. Department of Neuropsychiatry, NTT Medical Center Tokyo, Tokyo, Japan

    Takeshi Otowa

  9. Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

    Hitoshi Kuwabara

  10. Department of Neuropsychiatry, Teikyo University School of Medicine, Tokyo, Japan

    Mamoru Tochigi

  11. Laboratory of Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan

    Tsukasa Sasaki

  12. Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan

    Kazuhiko Nakamura

  13. Faculty of Contemporary Sociology, Chukyo University, Toyota, Aichi, Japan

    Masatsugu Tsujii

  14. Research Center for Child Mental Development, University of Fukui, Yoshida-gun, Fukui, Japan

    Hideo Matsuzaki

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  1. Shabeesh Balan
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Correspondence to Shabeesh Balan, Yoichi Shinkai or Takeo Yoshikawa.

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Dr. Toshihiro Endo is the founder and researcher at Phenovance Research & Technology LLC, Japan. Remaining all the authors have no conflicting interests to declare.

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Balan, S., Iwayama, Y., Ohnishi, T. et al. 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. Mol Psychiatry 26, 7550–7559 (2021). https://doi.org/10.1038/s41380-021-01199-7

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