Research projects

1. Cell fate commitment in neural stem cell lineages

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).

2. Temporospatial control of natural lineage 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., 2018, eLife).

Our lab seeks to understand the cellular and molecular mechanisms underlying self-renewal, migration and differentiation of normal and cancer stem cells. Stem cells yield promise for regenerative medicine but also pose huge challenges. It remains uncertain how to inhibit stem-cell-derived tumor formation without harming normal stem cells. It is likewise unclear how directional stem cell migration, a critical step in tissue regeneration, is orchestrated. Using newly-established or previously-unexplored stem cell models in Drosophila, we employ a convergence of fly genetics, cell biology, biochemistry and live imaging to investigate a few fundamental questions: 1) How normal stem cells within a specific tissue are maintained and how to distinguish normal from cancer stem cell? 2) During normal development and upon tissue injury, how guidance cues may be converted into physical movement of stem cells in a timely and directional manner? Since the fundamental principles we will unravel using relatively simple Drosophila stem cell models are likely to be highly conserved in human, knowledge obtained from our studies should provide new insight into new strategies for anti-cancer therapy and tissue regeneration.

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