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RNA-regulatory exosome complex confers cellular survival to promote erythropoiesis.

ABSTRACT: Cellular differentiation requires vast remodeling of transcriptomes, and therefore machinery mediating remodeling controls differentiation. Relative to transcriptional mechanisms governing differentiation, post-transcriptional processes are less well understood. As an important post-transcriptional determinant of transcriptomes, the RNA exosome complex (EC) mediates processing and/or degradation of select RNAs. During erythropoiesis, the erythroid transcription factor GATA1 represses EC subunit genes. Depleting EC structural subunits prior to GATA1-mediated repression is deleterious to erythroid progenitor cells. To assess the importance of the EC catalytic subunits Dis3 and Exosc10 in this dynamic process, we asked if these subunits function non-redundantly to control erythropoiesis. Dis3 or Exosc10 depletion in primary murine hematopoietic progenitor cells reduced erythroid progenitors and their progeny, while sparing myeloid cells. Dis3 loss severely compromised erythroid progenitor and erythroblast survival, rendered erythroblasts hypersensitive to apoptosis-inducing stimuli and induced γ-H2AX, indicative of DNA double-stranded breaks. Dis3 loss-of-function phenotypes were more severe than those caused by Exosc10 depletion. We innovated a genetic rescue system to compare human Dis3 with multiple myeloma-associated Dis3 mutants S447R and R750K, and only wild type Dis3 was competent to rescue progenitors. Thus, Dis3 establishes a disease mutation-sensitive, cell type-specific survival mechanism to enable a differentiation program.

SUBMITTER: Mehta C

PROVIDER: S-EPMC8450083 | biostudies-literature |

REPOSITORIES: biostudies-literature

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RNA-Regulatory Exosome Complex Confers Erythroid Progenitor Cell Survival and Activity In Vivo

Project description: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.

2022-09-26 | GSE203607 | GEO

Post-transcriptional control of cellular differentiation by the RNA exosome complex.

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| S-SCDT-EMBOJ-2019-102700 | biostudies-other

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