KAT6B is required for histone 3 lysine 9 acetylation and SOX gene expression in the developing brain

Bergamasco, MI; Abeysekera, W; Garnham, AL; Hu, Y; Li-Wai-Suen, CS; Sheikh, BN; Smyth, GK; Thomas, T; Voss, AK

Author(s): Bergamasco, MI; Abeysekera, W; Garnham, AL; Hu, Y; Li-Wai-Suen, CS; Sheikh, BN; Smyth, GK; Thomas, T; Voss, AK;
Details: Publication Year 2025-02,Volume 8,Issue #2,Page e202402969
Journal Title: Life Science Alliance
Abstract: Heterozygous mutations in the histone lysine acetyltransferase gene KAT6B (MYST4/MORF/QKF) underlie neurodevelopmental disorders, but the mechanistic roles of KAT6B remain poorly understood. Here, we show that loss of KAT6B in embryonic neural stem and progenitor cells (NSPCs) impaired cell proliferation, neuronal differentiation, and neurite outgrowth. Mechanistically, loss of KAT6B resulted in reduced acetylation at histone H3 lysine 9 and reduced expression of key nervous system development genes in NSPCs and the developing cortex, including the SOX gene family, in particular Sox2, which is a key driver of neural progenitor proliferation, multipotency and brain development. In the fetal cortex, KAT6B occupied the Sox2 locus. Loss of KAT6B caused a reduction in Sox2 promoter activity in NSPCs. Sox2 overexpression partially rescued the proliferative defect of Kat6b (-/-) NSPCs. Collectively, these results elucidate molecular requirements for KAT6B in brain development and identify key KAT6B targets in neural precursor cells and the developing brain.
Publisher: Life Sciene Alliance
Keywords: Animals; *Histones/metabolism; Acetylation; *Histone Acetyltransferases/metabolism/genetics; Mice; *Neural Stem Cells/metabolism/cytology; *Brain/metabolism/embryology; *Lysine/metabolism; *SOXB1 Transcription Factors/metabolism/genetics; Cell Proliferation/genetics; Gene Expression Regulation, Developmental/genetics; Cell Differentiation/genetics; Neurogenesis/genetics; Mice, Knockout; Promoter Regions, Genetic/genetics
Research Division(s): Bioinformatics; Epigenetics And Development
PubMed ID: 39537341
Publisher's Version: https://doi.org/10.26508/lsa.202402969
Open Access at Publisher's Site: https://doi.org/10.26508/lsa.202402969
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: e202402969.full.pdf - (4.14MB, application/pdf)

Creation Date: 2024-12-05 11:23:57

Last Modified: 2024-12-05 11:32:02