School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.
Space Environment Simulation Research Infrastructure, Harbin Institute of Technology, Harbin 150080, China.
Int J Mol Sci. 2022 Mar 21;23(6):3376. doi: 10.3390/ijms23063376.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disease. To date, more than 1000 genes have been shown to be associated with ASD, and only a few of these genes account for more than 1% of autism cases. Klf7 is an important transcription factor of cell proliferation and differentiation in the nervous system, but whether klf7 is involved in autism is unclear.
We first performed ChIP-seq analysis of klf7 in N2A cells, then performed behavioral tests and RNA-seq in klf7 mice, and finally restored mice with adeno-associated virus (AAV)-mediated overexpression of klf7 in klf7 mice.
Klf7 targeted genes are enriched with ASD genes, and 631 ASD risk genes are also differentially expressed in klf7 mice which exhibited the core symptoms of ASD. When klf7 levels were increased in the central nervous system (CNS) in klf7 adult mice, deficits in social interaction, repetitive behavior and majority of dysregulated ASD genes were rescued in the adults, suggesting transcriptional regulation. Moreover, knockdown of klf7 in human brain organoids caused dysregulation of 517 ASD risk genes, 344 of which were shared with klf7 mice, including some high-confidence ASD genes.
Our findings highlight a klf7 regulation of ASD genes and provide new insights into the pathogenesis of ASD and promising targets for further research on mechanisms and treatments.
自闭症谱系障碍（ASD）是一种复杂的神经发育疾病。迄今为止，已有 1000 多个基因被证明与 ASD 相关，而这些基因中只有少数几个占自闭症病例的 1%以上。Klf7 是神经系统细胞增殖和分化的重要转录因子，但 klf7 是否与自闭症有关尚不清楚。
我们首先对 N2A 细胞中的 klf7 进行 ChIP-seq 分析，然后在 klf7 小鼠中进行行为测试和 RNA-seq，最后用腺相关病毒（AAV）介导的 klf7 在 klf7 小鼠中的过表达来恢复 klf7 小鼠。
klf7 的靶向基因富集了 ASD 基因，631 个 ASD 风险基因在 klf7 小鼠中也存在差异表达，klf7 小鼠表现出 ASD 的核心症状。当 klf7 水平在 klf7 成年小鼠的中枢神经系统（CNS）中升高时，成年小鼠的社交互动、重复行为缺陷和大多数失调的 ASD 基因得到了挽救，提示存在转录调控。此外，在人类脑类器官中敲低 klf7 会导致 517 个 ASD 风险基因失调，其中 344 个与 klf7 小鼠共享，包括一些高可信度的 ASD 基因。
我们的研究结果强调了 klf7 对 ASD 基因的调控作用，为 ASD 的发病机制提供了新的见解，并为进一步研究机制和治疗方法提供了有希望的靶点。
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