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

Abstract

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.

Krüppel-like factor 7 deficiency causes autistic-like behavior in mice via regulating Clock gene

“…1 A), which peaked at CT16 and nadired at CT0 (CT0 is the onset at the lighting period). In our previous study [ 10 ], we found that the target genes of klf7 were significantly enriched in circadian rhythms. In order to confirm the effects of klf7 on circadian rhythm genes, we knocked down klf7 level in N2A cells with a lentiviral short hairpin RNA (shRNA).…”

“…5 D). In our previous study [ 10 ], klf7 ± mice showed the mild autistic behavior, which could be improved if klf7 is expressed in the brain by the adeno-associated virus. So we also performed the RNA-seq on klf7 ± mice treated with adeno-associated virus, and analyzed the expression level of rhythm genes in the brain of klf7 ± mice before and after treatment.…”

“…Our results showed that increased klf7 level could reverse the expression level of rhythm genes (Fig. 5 E) and rescue the autistic behavior [ 10 ]. These results suggest that klf7 is an important member involved in the regulation of rhythmic circadian genes in vivo and links circadian rhythms to ASD (Fig.…”

“…These studies suggest a possible link between klf7 mutation and ASD. In our recent study, klf7 was confirmed to be an autism-related gene by constructing Nestin-Cre conditional knockout mouse model, though the mechanism behind remains unknown [ 10 ].…”

“…Klf7 was identified as a regulator related to suprachiasmatic nucleus function and could enrich rhythm genes in mouse suprachiasmatic nucleus [ 11 , 12 ]. In this regard, we also discovered that target genes of both human klf7 and mouse klf7 were significantly enriched in circadian rhythms [ 10 ], indicating that klf7 is involved in circadian rhythm. More evidences have been recently collected to support the strong link between dysregulated circadian rhythm and ASD.…”