Dynamic phosphorylation of FOXA1 by Aurora B guides post-mitotic gene reactivation

• Published in: Cell reports (Cambridge) 2024-09, Vol.43 (9), p.114739, Article 114739
• Main Authors: Zhang, Ting, Liu, Shuaiyu, Durojaye, Olanrewaju, Xiong, Fangyuan, Fang, Zhiyou, Ullah, Tahir, Fu, Chuanhai, Sun, Bo, Jiang, Hao, Xia, Peng, Wang, Zhikai, Yao, Xuebiao, Liu, Xing
• Format: Article
• Language: English
• Subjects: Aurora B; biomolecular condensation; bookmarking factor; CP: Cell biology; FOXA1; gene reactivation; mitosis; phosphorylation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114739

FOXA1 serves as a crucial pioneer transcription factor during developmental processes and plays a pivotal role as a mitotic bookmarking factor to perpetuate gene expression profiles and maintain cellular identity. During mitosis, the majority of FOXA1 dissociates from specific DNA binding sites and redistributes to non-specific binding sites; however, the regulatory mechanisms governing molecular dynamics and activity of FOXA1 remain elusive. Here, we show that mitotic kinase Aurora B specifies the different DNA binding modes of FOXA1 and guides FOXA1 biomolecular condensation in mitosis. Mechanistically, Aurora B kinase phosphorylates FOXA1 at Serine 221 (S221) to liberate the specific, but not the non-specific, DNA binding. Interestingly, the phosphorylation of S221 attenuates the FOXA1 condensation that requires specific DNA binding. Importantly, perturbation of the dynamic phosphorylation impairs accurate gene reactivation and cell proliferation, suggesting that reversible mitotic protein phosphorylation emerges as a fundamental mechanism for the spatiotemporal control of mitotic bookmarking. [Display omitted] •FOXA1 is phosphorylated at Serine 221 in the DNA binding domain by Aurora B in mitosis•FOXA1 phosphorylation impairs the specific, but not the non-specific, DNA binding•FOXA1 forms specific DNA-dependent condensates, which are disrupted by phosphorylation•Dynamic FOXA1 phosphorylation regulates transcription reactivation and cell proliferation Zhang et al. discovered that bookmarking factor FOXA1 undergoes dynamic phosphorylation at Serine 221 by Aurora B during mitosis, orchestrating its different DNA binding patterns and the periodic FOXA1 condensate formation during the cell cycle. Moreover, this phosphorylation regulates the target gene reactivation post-mitosis and cancer cell proliferation.