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

2020 Fiscal Year Annual Research Report

• Project/Area Number: 19K08084
• 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
• Keywords: Autism / H3K9 trimethylation / SUV39H2 / protocadherin b cluster / behavioral flexibility

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: - Pages: -
  • Peer Reviewed / Int'l Joint Research