Mitotic Implantation of the Transcription Factor Prospero via Phase Separation Drives Terminal Neuronal Differentiation

• Published in: Developmental cell 2020-02, Vol.52 (3), p.277-293.e8
• Main Authors: Liu, Xiaodan, Shen, Jingwen, Xie, Leiming, Wei, Zelin, Wong, Chouin, Li, Yiyao, Zheng, Xinhe, Li, Pilong, Song, Yan
• Format: Article
• Language: English
• Subjects: Drosophila melanogaster; H3K9me3; heterochromatin condensation; HP1; liquid-liquid phase separation; mitotic retention; neural precursors; neural stem cells; neuronal differentiation; Prospero/Prox1
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2019.11.019

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. [Display omitted] •Liquid-liquid phase separation drives mitotic implantation of transcription factor Pros•Mitotic retention is crucial for Pros to promote terminal neuronal differentiation•Pros condensates and expands H3K9me3+ heterochromatin domains in neurons•Pros recruits and concentrates HP1a into phase-separated condensates Liu et al. show that the transcription factor Prospero is retained at mitotic chromosomes of neural precursors via liquid-liquid phase separation, where it recruits and condensates HP1, driving heterochromatin domain expansion and terminal neuronal differentiation.