RNA-regulatory exosome complex suppresses an apoptotic program to confer erythroid progenitor cell survival in vivo

• Published in: Blood advances 2023-02, Vol.7 (4), p.586-601
• Main Authors: Fraga de Andrade, Isabela, Johnson, Kirby D., Mehta, Charu, Dewey, Colin N., Basu, Uttiya, Bresnick, Emery H.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Erythroid Precursor Cells; Exosome Multienzyme Ribonuclease Complex; Exosomes; Mice; Red Cells, Iron, and Erythropoiesis; RNA
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2022008481

•Exosc3 expression in the hematopoietic system is essential for mouse embryogenesis.•Exosc3 confers erythroid progenitor survival and activity in vivo by suppressing an apoptotic gene expression program. [Display omitted] The RNA-regulatory exosome complex (EC) posttranscriptionally and cotranscriptionally 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 used the hematopoietic-specific Vav1-Cre and “conditional by inversion” mouse system to ablate Exosc3, encoding an EC structural subunit. Although Exosc3C/C Cre+ embryos developed normally until embryonic day 14.5, Exosc3 ablation was embryonic lethal and severely reduced erythromyeloid progenitor activity. RNA sequencing analysis of Exosc3-ablated burst-forming unit-erythroid revealed elevated transcripts encoding multiple proapoptotic 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.