During development, the neural epithelium gives rise to the cellular diversity of the brain and nervous system. Neural stem cells (NSCs) are formed and persist into adulthood to act as a cellular reservoir for adult neurogenesis. Despite the requirement for the continued replenishment of the cells that comprise adult neural networks, the factors and mechanisms that regulate NSCs in vivo, remain poorly understood.
The MYST family histone acetyltransferase KAT6B (MYST4, QKF) plays essential roles in the developing cortex, with de novo, heterozygous mutations in the human KAT6B gene underlying five intellectual disability disorders. However, the mechanisms by which KAT6B impairment results in intellectual disability remain unknown.
Here, we demonstrate that KAT6B directs NSC proliferation and differentiation in vivo and in vitro. Cultured Kat6b–/– NSCs show impaired proliferation and reduced neurogenesis and neurite outgrowth. Conversely, Kat6b overexpression enhances NSC proliferation and neuronal differentiation in vitro. We show that KAT6B regulates key NSC pluripotency and neurogenesis pathways and identify KAT6B as a novel regulator of a family of transcription factors, including pioneer transcription factors. We demonstrate that overexpression of a pioneer transcription factor partially rescues the proliferation defect in Kat6b–/– NSCs and suggests that pioneer transcription factors cannot exert their full effect without KAT6B.
Taken together, our results identify KAT6B as an essential facilitator of neurogenesis, upstream of pioneer transcription factors and suggest that chromatin organisation by KAT6B is critical for establishing a permissive state for neuronal differentiation.