Histone acetyltransferase KAT2A modulates neural stem cell differentiation and proliferation by inducing degradation of the transcription factor PAX6

Neural stem cells (NSCs) proliferation and differentiation rely on proper expression and posttranslational modification of transcription factors involved in the determination of cell fate. Further characterization is needed to connect modifying enzymes with their transcription factor substrates in the regulation of these processes. Here, we demonstrated that the inhibition of KAT2A, a histone acetyltransferase, leads to a phenotype of small eyes in the developing embryo of zebrafish, which is associated with enhanced proliferation and apoptosis of NSCs in zebrafish eyes. We confirmed that this phenotype is mediated by the elevated level of PAX6 protein. We further verified that KAT2A negatively regulates PAX6 at the protein level in cultured neural stem cells of rat cerebral cortex. We revealed that PAX6 is a novel acetylation substrate of KAT2A and the acetylation of PAX6 promotes its ubiquitination mediated by the E3 ligase RNF8 that facilitated PAX6 degradation. Our study proposes that KAT2A inhibition results in accelerated proliferation, delayed differentiation, or apoptosis, depending on the context of PAX6 dosage. Thus, the KAT2A/ PAX6 axis plays an essential role to keep a balance between the self-renewal and differentiation of NSCs.

Automated summary

The proliferation and differentiation of neural stem cells (NSCs) rely on the proper expression and posttranslational modifications of transcription factors. In this study, we demonstrated that inhibition of the histone acetyltransferase KAT2A led to small eyes in developing zebrafish embryos, associated with increased proliferation and apoptosis of NSCs in zebrafish eyes. We found that the elevated level of PAX6 protein mediated this phenotype, and further confirmed that KAT2A negatively regulates PAX6 at the protein level in cultured rat cerebral cortex neural stem cells. Our study revealed that PAX6 is a novel acetylation substrate of KAT2A, and its acetylation promotes ubiquitination and degradation of PAX6. The KAT2A/PAX6 axis plays a crucial role in maintaining a balance between self-renewal and differentiation of NSCs.