Loss of NSD2 causes dysregulation of synaptic genes and altered H3K36 dimethylation in mice [ChIP-seq]

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. We performed transcriptomic and epigenetic analyses using Nsd2 knockout mice to better understand the role of NSD2 in the brain. 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. ChIP-seq was performed for H3K36me2 in WT and Nsd2 KO E15.5 brain.

表观遗传紊乱已被证实与神经发育障碍密切相关。NSD2与发育迟缓、智力障碍存在关联，但其在大脑发育及功能调控中的具体作用仍不明确。为深入解析NSD2在大脑中的功能机制，本研究利用Nsd2敲除小鼠开展了转录组学与表观遗传学分析。转录组学分析结果显示，NSD2缺失会导致与突触传递及突触形成相关的基因表达失调。通过分析H3赖氨酸36二甲基化（H3 lysine 36 dimethylation, H3K36me2）的变化，我们发现NSD2介导的H3K36me2主要标记静息状态染色质区域，且H3K36me2的重新分布发生在转录基因与增强子区域。整合转录组学与表观基因组学数据后，我们观察到，在部分与突触传递及突触形成相关的失调基因中，存在H3K36me2水平的显著改变。上述结果表明，NSD2可通过调控H3K36me2修饰参与对神经功能至关重要的基因表达调控。本研究结果为阐明NSD2的生物学功能提供了新的视角，同时深化了我们对大脑表观遗传调控机制的认知。本研究针对野生型（Wild Type, WT）与Nsd2敲除（Knockout, KO）小鼠胚胎第15.5天的脑组织，开展了H3K36me2的染色质免疫共沉淀测序（Chromatin Immunoprecipitation Sequencing, ChIP-seq）实验。