Dynamics of Ribosomal RNA Transcription and Abundance in Normal and Leukemic Hematopoiesis

Abstract

Transcription of ribosomal RNAs (rRNAs) from rDNA repeats is a critical first step of ribosome biogenesis. Often deemed a housekeeping process, its cell-type-specific regulation is largely unexplored. We profiled nascent rRNA and mature rRNAs (ribosome subunits) across mouse hematopoiesis, and observed 10-fold, cell-type-specific variation in rRNA abundance that is largely uncoupled from proliferation and translation rates. We also tested and confirmed the longstanding assumption that acute myeloid leukemia progenitors show notably higher rRNA levels than matched normal counterparts. These trends in nascent rRNA across hematopoietic contexts parallel changes in the proportion of active rDNA repeats. Absolute quantification of rRNAs unexpectedly revealed an excess of large versus small ribosomal subunits in all cells, particularly in the myeloid lineage. Finally, using an RNA Polymerase I degron system, we found that reduced rRNA transcription promotes myeloid progenitor differentiation. Collectively, our work uncovers complex dynamics and functional significance of rRNA regulation in hematopoiesis.