Loss of NSD2 causes dysregulation of synaptic genes and altered H3K36 dimethylation in mice

Shiori Kinoshita; Kazuaki Kojima; Eriko Ohnishi; Yuka Takayama; Hiroki Kikuchi; Shuji Takada; Kazuhiko Nakabayashi; Tomoko Kawai; Kenichiro Hata

doi:10.3389/fgene.2024.1308234

Loss of NSD2 causes dysregulation of synaptic genes and altered H3K36 dimethylation in mice

Front Genet. 2024 Feb 14:15:1308234. doi: 10.3389/fgene.2024.1308234. eCollection 2024.

Authors

Affiliations

¹ Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
² Department of NCCHD Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
³ Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan.
⁴ Department of Human Molecular Genetics, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.

Abstract

Background: Epigenetic disruptions have been implicated in neurodevelopmental disorders. NSD2 is associated with developmental delay/intellectual disability; however, its role in brain development and function remains unclear. Methods: We performed transcriptomic and epigenetic analyses using Nsd2 knockout mice to better understand the role of NSD2 in the brain. Results and discussion: Transcriptomic analysis revealed that the loss of NSD2 caused dysregulation of genes related to synaptic transmission and formation. By analyzing changes in H3 lysine 36 dimethylation (H3K36me2), NSD2-mediated H3K36me2 mainly marked quiescent state regions and the redistribution of H3K36me2 occurred at transcribed genes and enhancers. By integrating transcriptomic and epigenetic data, we observed that H3K36me2 changes in a subset of dysregulated genes related to synaptic transmission and formation. These results suggest that NSD2 is involved in the regulation of genes important for neural function through H3K36me2. Our findings provide insights into the role of NSD2 and improve our understanding of epigenetic regulation in the brain.

Keywords: ChIP sequencing; H3K36me2; NSD2; RNA sequencing; neurodevelopmental disorder.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by AMED (JP22ek0109489 to KH and JP19ek0109205 to TK), JSPS KAKENHI (JP21H02887 and JP21K19584 to KH), the National Center for Child Health and Development (NCCHD 2022A-3 to KH), and Gunma University for the promotion of scientific research (to KH).