Histone lysine methyltransferase Pr-set7/SETD8 promotes neural stem cell reactivation.

Jiawen Huang, Mahekta R Gujar, Qiannan Deng, Sook Y Chia, Song Li, Patrick Tan, Wing-Kin Sung, Hongyan Wang

EMBO reports 2021 Apr 07

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The ability of neural stem cells (NSCs) to switch between quiescence and proliferation is crucial for brain development and homeostasis. Increasing evidence suggests that variants of histone lysine methyltransferases including KMT5A are associated with neurodevelopmental disorders. However, the function of KMT5A/Pr-set7/SETD8 in the central nervous system is not well established. Here, we show that Drosophila Pr-Set7 is a novel regulator of NSC reactivation. Loss of function of pr-set7 causes a delay in NSC reactivation and loss of H4K20 monomethylation in the brain. Through NSC-specific in vivo profiling, we demonstrate that Pr-set7 binds to the promoter region of cyclin-dependent kinase 1 (cdk1) and Wnt pathway transcriptional co-activator earthbound1/jerky (ebd1). Further validation indicates that Pr-set7 is required for the expression of cdk1 and ebd1 in the brain. Similar to Pr-set7, Cdk1 and Ebd1 promote NSC reactivation. Finally, overexpression of Cdk1 and Ebd1 significantly suppressed NSC reactivation defects observed in pr-set7-depleted brains. Therefore, Pr-set7 promotes NSC reactivation by regulating Wnt signaling and cell cycle progression. Our findings may contribute to the understanding of mammalian KMT5A/PR-SET7/SETD8 during brain development. © 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Citation

Jiawen Huang, Mahekta R Gujar, Qiannan Deng, Sook Y Chia, Song Li, Patrick Tan, Wing-Kin Sung, Hongyan Wang. Histone lysine methyltransferase Pr-set7/SETD8 promotes neural stem cell reactivation. EMBO reports. 2021 Apr 07;22(4):e50994