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

• Project/Area Number: 19K08084
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: 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)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Autism / H3K9 trimethylation / SUV39H2 / protocadherin b cluster / behavioral flexibility / autism / H3K9 methyltransferase / variant / behavior / HistoneMethyltransferase / Autism Spectrum Disorder / Suv39h2 / H3K9

Outline of Research at the Start

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.

Outline of Annual Research Achievements

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.

Research Products

• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: Molecular Psychiatry Volume: -
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Evidence for Altered Metabolism of Sphingosine-1-phosphate in the Corpus Callosum of Patients with Schizophrenia (2020)
  • Author(s): Esaki, K., Balan, S., Iwayama, Y., Shimamoto-Mitsuyama, C., Hirabayashi, Y., Dean, B. & Yoshikawa, T.
  • Journal Title: Schizophrenia Bulletin Volume: - Issue: 5 Pages: 1172-1181
  • DOI: 10.1093/schbul/sbaa052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology. (2019)
  • Author(s): Ide M, et al. .... Kimura H, Yoshikawa T.
  • Journal Title: EMBO Mol Med. Volume: 11(12) Issue: 12
  • DOI: 10.15252/emmm.201910695
  • NAID: 120007132855
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis (2019)
  • Author(s): Toyoshima M, Jiang X, Ogawa T, Ohnishi T, Yoshihara S, Balan S, Yoshikawa T, Hirokawa N.
  • Journal Title: Life Sci Alliance Volume: 2 Issue: 5 Pages: e201900478-e201900478
  • DOI: 10.26508/lsa.201900478
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Investigation of betaine as a novel psychotherapeutic for schizophrenia. (2019)
  • Author(s): 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.
  • Journal Title: EBioMedicine Volume: 45 Pages: 432-446
  • DOI: 10.1016/j.ebiom.2019.05.062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of the role of fatty acid-binding protein 7 in controlling schizophrenia-relevant phenotypes using newly established knockout mice (2019)
  • Author(s): Shimamoto-Mitsuyama Chie、Ohnishi Tetsuo、Balan Shabeesh、Ohba Hisako、Watanabe Akiko、Maekawa Motoko、Hisano Yasuko、Iwayama Yoshimi、Owada Yuji、Yoshikawa Takeo
  • Journal Title: Schizophrenia Research Volume: - Pages: 52-59
  • DOI: 10.1016/j.schres.2019.02.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Genetic determinants of epigenetic modifications contributing to the ASD pathogenesis’ (2019)
  • Author(s): Shabeesh Balan
  • Organizer: Symposium on Autism at the 6th Congress of Asian College of Neuropsychopharmacology (AsCNP)
  • Int'l Joint Research / Invited