The RNA binding protein Ars2 supports hematopoiesis at multiple levels

Recent biochemical characterization of arsenic resistance protein 2 (Ars2) has established it as central in determining the fate of nascent ribonucleic acid (RNA) polymerase II (RNAPII) transcripts. Through interactions with the nuclear 5'-7-methylguanosine cap-binding complex, Ars2 promotes cotranscriptional processing coupled with nuclear export or degradation of several classes of RNAPII transcripts, allowing for gene expression programs that facilitate rapid and sustained proliferation of immortalized cells in culture. However, rapidly dividing cells in culture do not represent the physiological condition of the vast majority of cells in an adult mammal. To examine functions of Ars2 in a physiological setting, we generated inducible Ars2 knockout mice and found that deletion of Ars2 from adult mice resulted in defective hematopoiesis in bone marrow and thymus. Importantly, only some of this defect could be explained by the requirement of Ars2 for rapid proliferation, which we found to be cell-type specific in vivo. Rather, Ars2 was required for survival of developing thymocytes and for limiting differentiation of bone marrow resident long-term hematopoietic stem cells. As a result, Ars2 knockout led to rapid thymic involution and loss of the ability of mice to regenerate peripheral blood after myeloablation. These in vivo data demonstrate that Ars2 expression is important at several steps of hematopoiesis, likely because Ars2 acts on gene expression programs underlying essential cell fate decisions such as the decision to die,proliferate, or differentiate.