3060 – DOWNREGULATED STAUFEN1 COMPROMISES HEMATOPOIETIC STEM CELL ACTIVITY IN VIVO AND ELICITS EXPRESSION SIGNATURES CHARACTERISTIC OF CLINICAL ANEMIAS

Abstract

Proper regulation of RNA localization, fidelity and translation are fundamental mechanisms regulated by RNA-binding proteins (RBPs). Staufen, a double-stranded RBP, mediates asymmetric cell division in developing neural precursors; however, its role in normal hematopoiesis remains unclear. Here, we studied the role of both mammalian paralogs of Staufen and identify that Stau1, but not Stau2, is enriched in both hematopoietic stem cell (HSC) and erythroid populations and is functionally essential to HSC activity in vivo post-transplantation. Unbiased global profiling of transcriptome and proteome changes with Stau1 downregulation in the primitive hematopoietic compartment reveal expression signatures predictive of an immune/inflammatory-associated anemia, with post-transcriptional pathway analyses highlighting concordant loss of erythroid-promoting transcription factors and cell cycle regulators, gain of an expression state consistent with interferon-γ activity, enhanced levels of translational regulation and decreased ribosomal RNA processing. These findings position Stau1 as a potential guardian of HSC-driven erythropoiesis. Our data further highlight a rational foundation for future investigations into the role of Stau1 in aplastic anemia and/or paroxysmal nocturnal hemoglobinuria, and may widen the scope of post-transcriptional gene regulation into anemia pathogenesis.