Research projects

1. Transcription factor condensates and timely neuronal differentiation

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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 drives timely and irreversible neuronal terminal differentiation (Liu X, Shen J, et al., 2020, Dev Cell).

2. 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, Dev Cell).

3. Timely neural progenitor fate commitment and tumorigenesis

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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, et al., 2018a, eLife).

4. Temporospatial control of cell fate reprogramming

Natural lineage reprogramming, the conversion of one cell identity to another during normal development, although rare, occurs with high efficiency and temporospatial precision. These natural lineage conversion events provide powerful model systems for deciphering the mystery of cellular plasticity. We recently uncovered a natural midgut-to-renal lineage reprogramming event during fruit fly metamorphosis and identified a highly conserved protein called Cut as a crucial cell identity switch in this process. A steep gradient of a spatial molecule (called Wingless/Wg) intersects with a pulse of steroid hormone to induce Cut expression specifically in a small subset of fly midgut progenitors, precursors that produce functional midgut cells, and convert them into renal identity. Intriguingly, the temporal and spatial signals triggering this natural lineage reprogramming event likely intersect through an unexpected chromatin looping mechanism. The mechanism we unveiled here might represent a new and general paradigm governing cell fate or identity switch with high precision in space and time, and has promising implications for the development of regenerative medicine strategies. (Xu K, et al., 2018b, eLife).