赖氨酸去甲基化酶 KDM7A 能够去除组蛋白修饰 H3K9me1/2 和 H3K27me1/2。KDM7A 在基因表达方面发挥关键作用，并对包括肿瘤发生、代谢和胚胎发育在内的生物过程有贡献。然而，KDM7A 在哺乳动物神经系统中的功能仍然知之甚少。本研究通过应用 CUT&Tag-seq、RNA-seq 和小鼠模型，全面探究了 KDM7A 在神经细胞中的功能作用。在 N2A 细胞中敲低 Kdm7a 导致转录起始位点附近组蛋白修饰的改变以及大量基因表达的变化。特别是，此敲低导致立即早期基因 (IEGs) 的表达显著下调，这一系列基因维持神经系统功能并与神经系统疾病相关。此外，通过基于腺相关病毒 (AAV) 的立体定向微注射实现小鼠海马齿状回 (DG) 神经元中 Kdm7a 敲低，结果显示 c-Fos 的表达显著下降，而 c-Fos 是神经元活动的标志物。小鼠的行为实验进一步揭示 Kdm7a 在海马体敲低抑制神经元活动，导致情绪和记忆的受损。总体而言，本研究揭示了 KDM7A 通过调节 IEGs 影响神经元功能，这可能为理解神经系统疾病的表观遗传机制提供新线索。 © 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

Lysine demethylase KDM7A removes histone modifications H3K9me1/2 and H3K27me1/2. KDM7A plays critical roles in gene expression and contribute to biological processes including tumorigenesis, metabolism, and embryonic development. However, the functions of KDM7A in mammalian nervous system are still poorly explored. In this study, functional roles of KDM7A are comprehensively investigated in neuronal cells by applying CUT&Tag-seq, RNA-seq and mice models. Knockdown of Kdm7a in N2A cells result in the alteration of histone modifications near transcription start sites (TSSs) and the expression changes of a large number of genes. In particular, the expression of immediate early genes (IEGs), a series of genes maintaining the function of the nervous system and associating with neurological disorders, are significantly decreased upon Kdm7a knockdown. Furthermore, in vivo knockdown of Kdm7a in dentate gyrus (DG) neuron of mice hippocampus, via Adeno-associated virus (AAV)-based stereotaxic microinjection, led to a significant decrease of the expression of c-Fos, a marker of neuron activity. Behavior assays in mice further revealed that Kdm7a knockdown in hippocampus repress neuron activity, which leading to impairment of emotion and memory. Collectively, the study reveals that KDM7A affects neuron functions by regulating IEGs, which may provide new clues for understanding epigenetic mechanisms in neurological disorders.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.