Autism Spectrum Disorders (ASD) associated rare loss of function genetic variant in SUV39H2; a putative role of H3K9 methylation dynamics in ASD pathogenesis

• 研究課題/領域番号: 19K08084
• 研究種目: 基盤研究(C)
• 配分区分: 基金
• 応募区分: 一般
• 審査区分: 小区分52030:精神神経科学関連
• 研究機関: 国立研究開発法人理化学研究所
• 研究代表者: SHABEESH BALAN 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (70721588)
• 研究期間 (年度): 2019-04-01 – 2021-03-31
• 研究課題ステータス: 完了 (2020年度)
• 配分額: 4,290千円 (直接経費: 3,300千円、間接経費: 990千円); 2021年度: 1,040千円 (直接経費: 800千円、間接経費: 240千円); 2020年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円); 2019年度: 1,690千円 (直接経費: 1,300千円、間接経費: 390千円)
• キーワード: Autism / H3K9 trimethylation / SUV39H2 / protocadherin b cluster / behavioral flexibility / autism / H3K9 methyltransferase / variant / behavior / HistoneMethyltransferase / Autism Spectrum Disorder / Suv39h2 / H3K9

研究開始時の研究の概要

We identified the first case of rare SUV39H2 LoF variant in ASD, indicating the role of impaired H3K9 methylation in genes relevant for ASD pathogenesis. So, I intend to delineate role of identified LoF variant in determining H3K9 methylation dynamics, downstream target genes involved in ASD, and test ASD related behaviors in knock-in mice model.

研究実績の概要

Recent evidence has documented the potential roles of histone-modifying enzymes in autism spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) di-methylation 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. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which are 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. 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.

研究成果

• [雑誌論文] 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 (2021)
  • 著者名/発表者名: Balan S, Iwayama Y, Ohnishi T, Fukuda M, Shirai A, Yamada A, Weirich S, Schuhmacher MK, Vijayan DK, Endo T, Hisano Y, Kotoshiba K, Toyota T, Otowa T, Kuwabara H, Tochigi M, Watanabe A, Ohba H, Maekawa M, Toyoshima M, Sasaki T, Nakamura K, Tsujii M, Matsuzaki H, Zhang KYJ, Jeltsch A, Shinkai Y, Yoshikawa T
  • 雑誌名: Molecular Psychiatry 巻: -
  • 査読あり / 国際共著
• [雑誌論文] Evidence for Altered Metabolism of Sphingosine-1-phosphate in the Corpus Callosum of Patients with Schizophrenia (2020)
  • 著者名/発表者名: Esaki, K., Balan, S., Iwayama, Y., Shimamoto-Mitsuyama, C., Hirabayashi, Y., Dean, B. & Yoshikawa, T.
  • 雑誌名: Schizophrenia Bulletin 巻: - 号: 5 ページ: 1172-1181
  • DOI: 10.1093/schbul/sbaa052
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology. (2019)
  • 著者名/発表者名: Ide M, et al. .... Kimura H, Yoshikawa T.
  • 雑誌名: EMBO Mol Med. 巻: 11(12) 号: 12
  • DOI: 10.15252/emmm.201910695
  • NAID: 120007132855
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis (2019)
  • 著者名/発表者名: Toyoshima M, Jiang X, Ogawa T, Ohnishi T, Yoshihara S, Balan S, Yoshikawa T, Hirokawa N.
  • 雑誌名: Life Sci Alliance 巻: 2 号: 5 ページ: e201900478-e201900478
  • DOI: 10.26508/lsa.201900478
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Investigation of betaine as a novel psychotherapeutic for schizophrenia. (2019)
  • 著者名/発表者名: Ohnishi T, Balan S, Toyoshima M, Maekawa M, Ohba H, Watanabe A, Iwayama Y, Fujita Y, Tan Y, Hisano Y, Shimamoto-Mitsuyama C, Nozaki Y, Esaki K, Nagaoka A, Matsumoto J, Hino M, Mataga N, Hayashi-Takagi A, Hashimoto K, Kunii Y, Kakita A, Yabe H, Yoshikawa T.
  • 雑誌名: EBioMedicine 巻: 45 ページ: 432-446
  • DOI: 10.1016/j.ebiom.2019.05.062
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Evaluation of the role of fatty acid-binding protein 7 in controlling schizophrenia-relevant phenotypes using newly established knockout mice (2019)
  • 著者名/発表者名: Shimamoto-Mitsuyama Chie、Ohnishi Tetsuo、Balan Shabeesh、Ohba Hisako、Watanabe Akiko、Maekawa Motoko、Hisano Yasuko、Iwayama Yoshimi、Owada Yuji、Yoshikawa Takeo
  • 雑誌名: Schizophrenia Research 巻: - ページ: 52-59
  • DOI: 10.1016/j.schres.2019.02.002
  • 査読あり / オープンアクセス / 国際共著
• [学会発表] Genetic determinants of epigenetic modifications contributing to the ASD pathogenesis’ (2019)
  • 著者名/発表者名: Shabeesh Balan
  • 学会等名: Symposium on Autism at the 6th Congress of Asian College of Neuropsychopharmacology (AsCNP)
  • 国際学会 / 招待講演