2. Academic Validation
  3. 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

  • Mol Psychiatry. 2021 Dec;26(12):7550-7559. doi: 10.1038/s41380-021-01199-7.
Shabeesh Balan 1 2,  Yoshimi Iwayama 3,  Tetsuo Ohnishi 3 4,  Mikiko Fukuda 5,  Atsuko Shirai 5,  Ayumi Yamada 5,  Sara Weirich 6,  Maren Kirstin Schuhmacher 6,  Kalarickal Vijayan Dileep 7,  Toshihiro Endo 8,  Yasuko Hisano 3,  Kaoru Kotoshiba 5,  Tomoko Toyota 3,  Takeshi Otowa 9,  Hitoshi Kuwabara 10,  Mamoru Tochigi 11,  Akiko Watanabe 3,  Hisako Ohba 3,  Motoko Maekawa 3,  Manabu Toyoshima 3,  Tsukasa Sasaki 12,  Kazuhiko Nakamura 13,  Masatsugu Tsujii 14,  Hideo Matsuzaki 15,  Kam Y J Zhang 7,  Albert Jeltsch 6,  Yoichi Shinkai 16,  Takeo Yoshikawa 17
Affiliations

Affiliations

  • 1 Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan. [email protected].
  • 2 Neuroscience Research Laboratory, Institute of Mental Health and Neurosciences (IMHANS), Kozhikode, Kerala, India. [email protected].
  • 3 Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan.
  • 4 Department of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
  • 5 Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.
  • 6 Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, Stuttgart, Germany.
  • 7 Laboratory for Structural Bioinformatics, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.
  • 8 Phenovance Research and Technology LLC, Kashiwa, Chiba, Japan.
  • 9 Department of Neuropsychiatry, NTT Medical Center Tokyo, Tokyo, Japan.
  • 10 Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
  • 11 Department of Neuropsychiatry, Teikyo University School of Medicine, Tokyo, Japan.
  • 12 Laboratory of Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan.
  • 13 Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan.
  • 14 Faculty of Contemporary Sociology, Chukyo University, Toyota, Aichi, Japan.
  • 15 Research Center for Child Mental Development, University of Fukui, Yoshida-gun, Fukui, Japan.
  • 16 Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan. [email protected].
  • 17 Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan. [email protected].
PMID: 34262135 DOI: 10.1038/s41380-021-01199-7
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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