ALTERNATIVE POLYADENYLATION REGULATES HEMATOPOIETIC STEM CELL METABOLISM

Alternative Polyadenylation (APA) is emerging as an important regulatory mechanism controlling 3’-UTRs and thereby RNA and protein isoform expression. However, the relevance of APA in stem cell hierarchies in vivo remains unexplored. Here, we show that deregulation of the APA regulator Pabpn1 results in severe hematopoietic stem cell (HSC) defects. Furthermore, we performed low input 3’-sequencing and established bioinformatic pipelines to uncover dynamic APA patterns in numerous genes of HSCs and multipotent progenitors. The 3’-UTRs of HSCs undergo shortening upon transition from quiescence to proliferation during homeostasis and in response to inflammation as well as during HSC differentiation. Strikingly, we observe APA-mediated metabolic reprogramming upon HSC activation leading to an increase in glutaminolysis. This increase is mediated by APA regulators and required for proper HSC function. Inhibition of this metabolic adjustment by targeting APA-regulators leads to impaired HSC function and a partial block in differentiation. Our study establishes APA and associated adaptations of the glutamine metabolism as novel layers of regulation that orchestrate HSC behavior and commitment in the hematopoietic cascade.