Research

Our Research Overview

Our lab investigates the mechanisms of stem cell regulation and how dysregulation may lead to disease states. Specifically, we utilize the powerful Drosophila Melanogaster as our model system, due to its simple anatomy. This in conjunction with abundant genetic and genomic tools has proven to be well suited to study unrecognized regulatory mechanisms. We combine advanced imaging techniques, genetics, and multi-omics approaches to study germline stem cells (GSCs), factors that may play a role in cell fates, and chromatin architecture within the cells of normal tissues and diseased tissues. Our research is focused on a few areas, such as chromatin state dynamics, the roles of nuclear non-coding RNAs in stem cell function and changes in extracellular matrix during tissue regeneration. Ultimately, we aim to deepen our knowledge of disease progression and contribute to developing new approaches to disease therapies and prevention.

Left: Normal Drosophila testes, Right: Tumorous testes filled with stem-like cells.

Why is it important to understand how stem cells are regulated?

Understand how diseases occur. As stem cells have the capacity to divide long-term and keep producing tissue cells, their dysregulation results in many disease conditions, including cancers, tissue degeneration, and aging. Better understanding of these conditions helps us to develop new therapeutic strategies for uncurable diseases.

 

    What do we do?

    We use Drosophila melanogaster (fruit flies) as a model system with a combination of genetics and various imaging techniques, and multiOMICS approaches. Owing to a simple anatomy and abundant genetic tools, this system is especially suited to discover previously unrecognized regulatory mechanisms.

     

    Niche ligand diffusion ensures spatial control of the signal

    In the Drosophila testis, germline stem cells (GSCs) are continuously producing sperm throughout the fly’s lifetime. When a GSC divides in niche, one daughter cell remains a GSC, while the other daughter cell starts differentiation. Niche derived BMP ligand has been thought to only activate GSCs but not other daughter cells despite of physical proximity of these cells. Using genetically-encoded nanobodies called Morphotraps, we blocked diffusion of BMP ligand without interfering with niche-stem cell signaling. Unexpectedly, we found that the diffusible fraction of ligand has opposite effect on the cells located inside and outside of the niche. It requires to promote differentiation of cells outside of the niche, while maintaining stemness of the cells inside of the niche, thereby ensuring spatial control of the niche with a single factor.

    Current project is aiming to understand how the factor induces opposed responses in different cell types.

    Related publication https://www.nature.com/articles/s41467-024-45408-7

     

    Emerging function of somatic homolog pairing in stem cell regulation

    The pairing of homologous chromosomes is a fundamental process for meiotic recombination to exchange maternal and paternal genomic information. Homolog pairing also occurs in non-meiotic cells in a broad range of organisms including mammals. We recently found a change in the physical interaction of a homologous gene locus of a stem-cell specific protein, Signal transducer and activator of transcription 92E (Stat92E), during asymmetric division of GSCs. We found that the stat92E locus on two homologous chromosomes interacts closely (paired) in GSCs but becomes separated (unpaired) in the differentiating daughter cells. This "change" of pairing status seems to be required for prompt downregulation of this gene within next a couple of stages of differentiation. These results suggest a fascinating possibility that homolog pairing states is a potential mechanism that represents programmed gene expression changes which may occur in future. We are currently investigating more general roles of local homologous chromosome interaction on storage of cellar memory and cell fate determination.

     

    Related publication https://www.nature.com/articles/s41467-022-31737-y