GSE203607
RNA-Regulatory Exosome Complex Confers Erythroid Progenitor Cell Survival and Activity In Vivo
The RNA exosome complex (EC) confers post-transcriptional regulation by processing and degrading RNAs in a context-dependent manner. Although the EC functions in diverse cell types, its contributions to stem and progenitor cell development have not been widely studied.  Previously, we demonstrated that the transcriptional regulator of erythrocyte development GATA1 represses genes encoding EC subunits, and in vitro analyses implicated the EC in maintaining erythroid progenitors. EC loss promoted the transition of progenitors into differentiating erythroblasts. To determine if these mechanisms operate in vivo, we utilized a hematopoietic-specific Vav1-Cre mouse system to conditionally ablate Exosc3, encoding an EC structural subunit with a conserved RNA binding domain. Although Exosc3 fl/fl Cre+ embryos developed normally until E14.5, Exosc3 ablation was embryonic lethal, severely reduced erythro-myeloid progenitor activity and reduced immunophenotypic progenitors. Exosc3 ablation decreased Kit+ hematopoietic progenitors and the level of cell surface c-Kit. RNA-seq analysis of Exosc3-ablated BFU-E revealed elevated transcripts encoding pro-apoptotic factors, including BCL2 family members Bax, Puma and Noxa, the death receptor Fas, and p53 target genes. Exosc3-ablated BFU-E and CFU-E progenitors exhibited increased apoptosis. Although megakaryocyte-erythroid progenitor (MEP) levels were unaltered, they were functionally defective. We propose that the EC controls an ensemble of apoptosis-regulatory RNAs, thereby conferring erythroid progenitor survival and promoting developmental erythropoiesis in vivo. Overall design: RNA-seq gene expression analysis of BFU-E sorted from E14.5 fetal livers (n = 6: 2 from each of 3 litters)