Mitotic Implantation of the Transcription Factor Prospero via Phase Separation Drives Terminal Neuronal Differentiation
Mitotic Implantation of the Transcription Factor Prospero via Phase Separation Drives Terminal Neuronal Differentiation
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DOI：
10.1016/j.devcel.2019.11.019
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发表时间：
2020-02-10
影响因子：
11.8
通讯作者：
Song, Yan
中科院分区：
文献类型：
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作者：
Liu, Xiaodan;Shen, Jingwen;Song, Yan
致密的异染色质块在分化的细胞中普遍存在，并对细胞重编程构成障碍。在细胞分化过程中异染色质重塑是如何协调的仍然不清楚。在这里，我们发现，进化上保守的同源结构域转录因子Prospero（Pros）/Prox 1通过驱动异染色质结构域凝聚和扩展来确保神经元分化。有趣的是，在有丝分裂的果蝇神经前体中，Pros通过液-液相分离（LLPS）保留在染色体的H3 K9 me 3（+）着丝粒周围异染色质区域。在有丝分裂退出的神经前体，有丝分裂保留的亲招募和异染色质蛋白1（HP 1）到相分离的凝聚物浓缩和驱动异染色质压实。这建立了一个转录抑制的染色质环境，保证细胞周期退出和终末神经元分化。重要的是，哺乳动物Prox 1采用类似的“有丝分裂-增殖确保异染色质凝聚”策略来加强神经元分化。总之，我们的结果揭示了一个新的范例，即通过LLPS有丝分裂植入转录因子重塑H3 K9 me 3（+）异染色质，并驱动及时和不可逆的终末分化。
Compacted heterochromatin blocks are prevalent in differentiated cells and present a barrier to cellular reprogramming. It remains obscure how heterochromatin remodeling is orchestrated during cell differentiation. Here we find that the evolutionarily conserved homeodomain transcription factor Prospero (Pros)/Prox1 ensures neuronal differentiation by driving heterochromatin domain condensation and expansion. Intriguingly, in mitotically dividing Drosophila neural precursors, Pros is retained at H3K9me3(+) pericentromeric heterochromatin regions of chromosomes via liquid-liquid phase separation (LLPS). During mitotic exit of neural precursors, mitotically retained Pros recruits and concentrates heterochromatin protein 1 (HP1) into phase-separated condensates and drives heterochromatin compaction. This establishes a transcriptionally repressive chromatin environment that guarantees cell-cycle exit and terminal neuronal differentiation. Importantly, mammalian Prox1 employs a similar "mitotic-implantationensured heterochromatin condensation" strategy to reinforce neuronal differentiation. Together, our results unveiled a new paradigm whereby mitotic implantation of a transcription factor via LLPS remodels H3K9me3(+) heterochromatin and drives timely and irreversible terminal differentiation.