%0 Journal Article %1 Balan2021 %A Balan, Shabeesh %A Iwayama, Yoshimi %A Ohnishi, Tetsuo %A Fukuda, Mikiko %A Shirai, Atsuko %A Yamada, Ayumi %A Weirich, Sara %A Schuhmacher, Maren Kirstin %A Dileep, Kalarickal Vijayan %A Endo, Toshihiro %A Hisano, Yasuko %A Kotoshiba, Kaoru %A Toyota, Tomoko %A Otowa, Takeshi %A Kuwabara, Hitoshi %A Tochigi, Mamoru %A Watanabe, Akiko %A Ohba, Hisako %A Maekawa, Motoko %A Toyoshima, Manabu %A Sasaki, Tsukasa %A Nakamura, Kazuhiko %A Tsujii, Masatsugu %A Matsuzaki, Hideo %A Zhang, Kam Y. J. %A Jeltsch, Albert %A Shinkai, Yoichi %A Yoshikawa, Takeo %D 2021 %J Molecular Psychiatry %K %N 12 %P 7550--7559 %R 10.1038/s41380-021-01199-7 %T A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin $\beta$-cluster genes in the developing brain %U https://doi.org/10.1038/s41380-021-01199-7 %V 26 %X 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 $\beta$ (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.

@article{Balan2021, 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 $\beta$ (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.}, added-at = {2022-12-05T09:40:31.000+0100}, author = {Balan, Shabeesh and Iwayama, Yoshimi and Ohnishi, Tetsuo and Fukuda, Mikiko and Shirai, Atsuko and Yamada, Ayumi and Weirich, Sara and Schuhmacher, Maren Kirstin and Dileep, Kalarickal Vijayan and Endo, Toshihiro and Hisano, Yasuko and Kotoshiba, Kaoru and Toyota, Tomoko and Otowa, Takeshi and Kuwabara, Hitoshi and Tochigi, Mamoru and Watanabe, Akiko and Ohba, Hisako and Maekawa, Motoko and Toyoshima, Manabu and Sasaki, Tsukasa and Nakamura, Kazuhiko and Tsujii, Masatsugu and Matsuzaki, Hideo and Zhang, Kam Y. J. and Jeltsch, Albert and Shinkai, Yoichi and Yoshikawa, Takeo}, biburl = {https://puma.ub.uni-stuttgart.de/bibtex/259c76c86aa4d1bfb69ee7d174a4e84bd/ajeltsch}, day = 01, doi = {10.1038/s41380-021-01199-7}, interhash = {55fe5f22f25fd1a43577ddbc41f6bc67}, intrahash = {59c76c86aa4d1bfb69ee7d174a4e84bd}, issn = {1476-5578}, journal = {Molecular Psychiatry}, keywords = {}, month = dec, number = 12, pages = {7550--7559}, timestamp = {2022-12-05T08:40:31.000+0100}, title = {A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin $\beta$-cluster genes in the developing brain}, url = {https://doi.org/10.1038/s41380-021-01199-7}, volume = 26, year = 2021 }