Krüppel-like Transcription Factor 7 Is a Causal Gene in Autism Development

Background: 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. Methods: 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. Results: 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. Conclusions: 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.