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-implantation-ensured 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.

中文翻译：

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通过相分离的转录因子Prospero的有丝分裂植入驱动终末神经元分化。

致密异染色质块在分化细胞中普遍存在，并成为细胞重编程的障碍。仍然不清楚在细胞分化过程中如何异染色质重塑。在这里，我们发现进化上保守的同源域转录因子Prospero（Pros）/ Prox1通过驱动异染色质域凝结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通过液相-液相分离（LLPS）保留在染色体的H3K9me3 +着丝粒异染色质区域。在神经前体的有丝分裂退出过程中，有丝分裂保留的Pros募集异染色质蛋白1（HP1）并将其浓缩成相分离的冷凝液，并驱动异染色质压紧。这将建立转录抑制染色质环境，从而确保细胞周期退出和终末神经元分化。重要的是，哺乳动物Prox1采用类似的“有丝分裂植入确保异染色质凝结”策略来增强神经元分化。总之，我们的研究结果揭示了一种新的范例，即通过LLPS的有丝分裂植入转录因子可重塑H3K9me3 +异染色质并推动及时且不可逆的终末分化。