RESEARCH
Ribosomal Dynamics Control Cell Identity
For decades, the ribosome was regarded as a static and uniform machine, identical in every cell of an organism. Our work challenges this view. We now appreciate that ribosomes are dynamic and heterogeneous, with cell-type-specific compositions that confer unique translational capacities.
We explore ribosomal dynamics (mainly rRNA modification dynamics) as a fundamental layer of gene regulation that facilitates cell-type-specific translation programs which are essential for the establishment of cellular identity.
By combining advanced molecular approaches, genetic mouse models, and in vivo experimental systems, we dissect ribosome diversity and function across diverse biological contexts, including hematopoiesis (our main focus), spermatogenesis, aging (in mice, worms, and fish), and caste determination in bees.
The Malignant and Pre-malignant Ribosome
Ribosomopathies are inherited syndromes caused by mutations in ribosomal components. A hallmark of these syndromes is bone marrow failure, which is the leading cause of morbidity and mortality in affected patients. Impaired hematopoietic stem cell function not only compromises blood production but also increases the risk of progression to hematologic malignancies, including acute myeloid leukemia.
Our research seeks to define the molecular and cellular mechanisms by which ribosome dysfunction disrupts stem cell homeostasis, drives bone marrow failure, promotes pre-malignant states, and ultimately contributes to leukemogenesis
Exploring Translation as a Therapeutic Target for Leukemia
We are exploring new therapeutic opportunities for leukemia by targeting the cellular translation machinery, a central regulator of gene expression and cell fate. Using genome-wide CRISPRi screens, we systematically identify components of the translational machinery that are essential for diseased-cells' survival but dispensable in normal cells. By integrating these screens with clinically approved therapies, we uncover synthetic lethal interactions that reveal novel vulnerabilities.
Ribosomal Hijacking by Viruses
Pathogens, and especially viruses, hijack the host ribosome to promote their own replication and drive disease. We investigate the strategies viruses use to manipulate ribosome composition and function to meet their specific translational needs. Through these studies, we aim not only to deepen our understanding of viral infection but also to leverage viruses as powerful tools to uncover fundamental principles of ribosome function and translational control.
