RNA-Regulatory Exosome Complex Suppresses an Apoptotic Program to Confer Erythroid Progenitor Cell Survival In Vivo

Blood Adv. 2022 Sep 26;bloodadvances.2022008481. doi: 10.1182/bloodadvances.2022008481. Online ahead of print.

Abstract

The RNA exosome complex (EC) post-transcriptionally and co-transcriptionally processes and degrades RNAs in a context-dependent manner. Although the EC functions in diverse cell types, its contributions to stem and progenitor cell development are not well understood. Previously, we demonstrated that the transcriptional regulator of erythrocyte development GATA1 represses EC subunit genes, and the EC maintains erythroid progenitors in vitro. To determine if this mechanism operates in vivo, we utilized the hematopoietic-specific Vav1-Cre and "Conditional Inversion" (Coin = C) mouse system to ablate Exosc3, encoding an EC structural subunit. Although Exosc3C/C Cre+ embryos developed normally until E14.5, Exosc3 ablation was embryonic lethal and severely reduced erythro-myeloid progenitor activity. RNA-seq analysis of Exosc3-ablated BFU-E revealed elevated transcripts encoding multiple pro-apoptotic factors, and the mutant erythroid progenitors exhibited increased apoptosis. We propose that the EC controls an ensemble of apoptosis-regulatory RNAs, thereby promoting erythroid progenitor survival and developmental erythropoiesis in vivo.