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-- We are our Choices
Cell fate memory in brain development – mitotic bookmarking
How to remember? - TBP as a miotic bookmarker to preserve neural stem cell fate memory
How a cell “remember” its fate or identity across mitosis? In this work, we made an unexpected discovery that TATA-binding protein (TBP), via recruiting chromatin remodeler and increasing local chromatin accessibility, acts as a mitotic bookmarker to preserve neural stem cell (NSC) fate memory in neural development. We also successfully developed a new pipeline for enriching mitotic versus interphase cells in a drug synchronization-free manner, followed by low-input CUT&Tag-seq analysis. This new pipeline allowed us to capture gene loci mitotically-bound by TBP in NSCs dissociated from developing brains and is potentially very useful for in vivo studies of mitotic bookmarking in the future (Shen Y, et al., 2025, Molecular Cell).
How to forget? - Mitotically-retained Prospero condensates drive neuronal differentiation
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. We lately discovered that mitotic implantation of the evolutionarily conserved homeobox transcription factor Prospero, via liquid-liquid phase separation, remodels H3K9me3-dependent heterochromatin and epigenetically silences self-renewal genes, driving timely and irreversible neuronal terminal differentiation (Liu X, Shen J, et al., 2020, Developmental Cell).
How to remember & forget? – Dual bookmarking orchestrates differential propagation of cell fate memory
How cell fate memory is differentially propagated to sibling daughter cells adopting distinct cell fates? Our latest research 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. This study marks the first discovery that mitotic bookmarks can be utilized in a combinatorial manner. Through the spatiotemporal combination of mitotic bookmarks, the potential range of gene loci and cell types that can be marked is significantly expanded. This enables the precise storage and transgenerational inheritance of complex neural cell fate memories, thereby safeguarding the extraordinarily intricate and delicate process of brain construction (Zhang R, Liu J, et al., 2025, Nature Communications).
Cell fate decision in brain development and disease
Timely neural stem cell fate commitment and self-renewal
The Super Elongation Complex (SEC), best known for transcription elongation checkpoint control, drives Drosophila neural stem cell (NSC) fate commitment. SEC is highly expressed in NSCs, where it interacts directly with the Notch signaling pathway in a self-reinforcing feedback loop for timely stem cell fate lock-in. SEC inactivation leads to NSC loss, whereas its forced activation results in neural progenitor dedifferentiation and tumorigenesis (Liu K, et al., 2017, Developmental Cell).
Timely neural progenitor fate commitment and tumorigenesis
The molecular mechanisms that prevent cell-autonomous ectopic Notch signaling activation and deleterious cell fate decisions remain unclear. Our results unveiled a safeguard mechanism whereby retromer retrieves potentially harmful Notch receptors in a timely manner to prevent aberrant Notch activation-induced neural progenitor dedifferentiation and brain tumor formation. Intriguingly, the downregulation of retromer components have been reported in various human cancers. Our studies thus also provide a new and unexpected link between the retromer complex and human cancers. (Li B, Wong C, et al., 2018, eLife).
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School of Life Sciences; Center for Life Sciences, Peking University, Beijing, China 100871
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