Zhang Rulan, Liu Jie, Zhang Zimo, Chen Zili, Wang Tanpeng, Shen Yuying, Lan Zejun, Chu Jingyi, Tang Haoxuan, Zhang Xiyue, Song Yan
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China.
The J. David Gladstone Institutes, 1650 Owens St, San Francisco, CA, 94158, USA.
Nat Commun. 2025 Aug 25;16(1):7930. doi: 10.1038/s41467-025-62974-6.
In brain development, neural stem cells (NSCs) undergo asymmetric cell divisions to replicate themselves and meanwhile produce differentiating siblings. It remains obscure how NSCs preserve their self-renewing fate across mitosis. Even less is known how cell fate memory is differentially propagated to sibling daughter cells adopting distinct cell fates. Here we found that key differentiation genes are dually bookmarked by pioneer factor GAF (GAGA factor) and H3K27ac in asymmetrically-dividing Drosophila central brain NSCs. In daughter cells adopting NSC fate, GAF promotes self-renewal through timely inhibiting differentiation genes via HDAC1-mediated H3K27 deacetylation, whereas in sibling daughter cells adopting neural progenitor fate, GAF occupancy is replaced by competitor SWI/SNF complex, allowing retention of H3K27ac mark and fast activation of differentiation genes. Thus, our study unveils a paradigm by which cell fate memory can be differentially transmitted to sibling daughter cells via dual antagonistic mitotic bookmarking and selective molecular competition mechanism.
在大脑发育过程中，神经干细胞（NSCs）进行不对称细胞分裂以自我复制，同时产生分化的子代细胞。目前尚不清楚神经干细胞如何在有丝分裂过程中维持其自我更新的命运。对于细胞命运记忆如何以不同方式传递给采用不同细胞命运的子代细胞，人们了解得更少。在这里，我们发现关键分化基因在不对称分裂的果蝇中枢脑NSCs中由先驱因子GAF（GAGA因子）和H3K27ac双重标记。在采用NSC命运的子代细胞中，GAF通过HDAC1介导的H3K27去乙酰化及时抑制分化基因来促进自我更新，而在采用神经祖细胞命运的子代细胞中，GAF的占据被竞争蛋白SWI/SNF复合体取代，从而保留H3K27ac标记并快速激活分化基因。因此，我们的研究揭示了一种范式，即细胞命运记忆可以通过双重拮抗的有丝分裂标记和选择性分子竞争机制以不同方式传递给子代细胞。
