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
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 syst...
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Published in | Molecular psychiatry Vol. 26; no. 12; pp. 7550 - 7559 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Nature Publishing Group
01.12.2021
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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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AbstractList | 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. |
Author | Maekawa, Motoko Schuhmacher, Maren Kirstin Shinkai, Yoichi Fukuda, Mikiko Tochigi, Mamoru Yoshikawa, Takeo Tsujii, Masatsugu Zhang, Kam Y J Balan, Shabeesh Otowa, Takeshi Iwayama, Yoshimi Weirich, Sara Kuwabara, Hitoshi Ohba, Hisako Hisano, Yasuko Shirai, Atsuko Toyoshima, Manabu Ohnishi, Tetsuo Sasaki, Tsukasa Dileep, Kalarickal Vijayan Jeltsch, Albert Yamada, Ayumi Kotoshiba, Kaoru Matsuzaki, Hideo Endo, Toshihiro Nakamura, Kazuhiko Watanabe, Akiko Toyota, Tomoko |
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Toshihiro surname: Endo fullname: Endo, Toshihiro organization: Phenovance Research and Technology LLC, Kashiwa, Chiba, Japan – sequence: 11 givenname: Yasuko surname: Hisano fullname: Hisano, Yasuko organization: Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan – sequence: 12 givenname: Kaoru surname: Kotoshiba fullname: Kotoshiba, Kaoru organization: Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan – sequence: 13 givenname: Tomoko surname: Toyota fullname: Toyota, Tomoko organization: Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan – sequence: 14 givenname: Takeshi surname: Otowa fullname: Otowa, Takeshi organization: Department of Neuropsychiatry, NTT Medical Center Tokyo, Tokyo, Japan – sequence: 15 givenname: Hitoshi surname: Kuwabara fullname: Kuwabara, Hitoshi organization: Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan – sequence: 16 givenname: Mamoru surname: Tochigi fullname: Tochigi, Mamoru organization: Department of Neuropsychiatry, Teikyo University School of Medicine, Tokyo, Japan – sequence: 17 givenname: Akiko surname: Watanabe fullname: Watanabe, Akiko organization: Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan – sequence: 18 givenname: Hisako surname: Ohba fullname: Ohba, Hisako organization: Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan – sequence: 19 givenname: Motoko surname: Maekawa fullname: Maekawa, Motoko organization: Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan – sequence: 20 givenname: Manabu surname: Toyoshima fullname: Toyoshima, Manabu organization: Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan – sequence: 21 givenname: Tsukasa surname: Sasaki fullname: Sasaki, Tsukasa organization: Laboratory of Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan – sequence: 22 givenname: Kazuhiko surname: Nakamura fullname: Nakamura, Kazuhiko organization: Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan – sequence: 23 givenname: Masatsugu surname: Tsujii fullname: Tsujii, Masatsugu organization: Faculty of Contemporary Sociology, Chukyo University, Toyota, Aichi, Japan – sequence: 24 givenname: Hideo orcidid: 0000-0002-6869-1261 surname: Matsuzaki fullname: Matsuzaki, Hideo organization: Research Center for Child Mental Development, University of Fukui, Yoshida-gun, Fukui, Japan – sequence: 25 givenname: Kam Y J orcidid: 0000-0002-9282-8045 surname: Zhang fullname: Zhang, Kam Y J organization: Laboratory for Structural Bioinformatics, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan – sequence: 26 givenname: Albert orcidid: 0000-0001-6113-9290 surname: Jeltsch fullname: Jeltsch, Albert organization: Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, Stuttgart, Germany – sequence: 27 givenname: Yoichi surname: Shinkai fullname: Shinkai, Yoichi email: yshinkai@riken.jp organization: Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan. yshinkai@riken.jp – sequence: 28 givenname: Takeo orcidid: 0000-0003-2791-6679 surname: Yoshikawa fullname: Yoshikawa, Takeo email: takeo.yoshikawa@riken.jp organization: Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan. takeo.yoshikawa@riken.jp |
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SubjectTerms | Animals Autism Autistic Disorder Brain - metabolism Cerebellum DNA methylation Embryos Enzymatic activity Etiology Genetic diversity Histone H3 Histone methyltransferase Histone-Lysine N-Methyltransferase - genetics Histone-Lysine N-Methyltransferase - metabolism Histones - genetics Histones - metabolism Hydrophobicity Hyperactivity Lysine Mice Neurodevelopment Next-generation sequencing Protocadherin Protocadherins |
Title | 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 |
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