Ribosome Heterogeneity as a Determinant of Cellular Identity in Hematopoiesis and Leukemia

Differentiation and acquisition of cell identity are fundamental processes in multi-cellular organisms. It is well established that chromatin and RNA mechanisms regulate cell fate determination.

Mounting evidence from our lab and others, however, suggests that translation is an additional, until now underappreciated, determinant of cell fate.

The importance of translation to differentiation can be gleaned from the hematopoietic system, where a prominent feature of human congenital syndromes, due to mutated ribosomes, is aberrant blood production. Crucially, these mutations lead to distinct cell-type-specific differentiation defects, rather than systemic failure.

It remains unclear how congenital (total-body) ribosomal mutations only affect particular differentiation paths and manifest in a cell-type-specific fashion.

We hypothesize that cell-type-specific ribosomal compositioni.e., ribosome heterogeneityresults in cell-type-specific translation profiles, and therefore represents a crucial layer of gene regulation in cell-fate and differentiation.

We will explore this hypothesis by pursuing three complementary objectives: (1) Systematically map ribosome heterogeneity and reveal its function in normal hematopoiesis and leukemia; (2) Determine how ribosome heterogeneity controls cell-type-specific translatomes and contributes to cellular transformation; and (3) Explore ribosome heterogeneity at single-cell resolution, using novel methodologies we will develop for simultaneous transcription and translatome interrogation.

By combining cutting-edge sequencing techniques with extensive genetic manipulations in physiological settings, we will reveal cell-type-specific translation, controlled by cell-type-specific ribosomes, as major regulators of cell fate in health and disease.

Understanding the mechanisms of cell-type-specific translation will provide a new paradigm for elucidating gene expression regulation and for revealing new mechanisms for human diseases.