USB1 deficiency disrupts neutrophil maturation via RNA dysregulation independent of global pre-mRNA splicing

U6 biogenesis 1 (USB1) gene mutations cause poikiloderma with neutropenia (PN), which is clinically characterized by skin hyperpigmentation, nail dysplasia, neutropenia, and an elevated risk of cancer. USB1 functions as an RNA exonuclease involved in RNA maturation and stability regulation, although its precise mechanism of action in the hematopoietic system remains unclear.

We established a myeloid cell-specific USB1 knockout mouse model (USB1fl/fl-Lyz2-cre) using CRISPR/Cas9. Using a combination of research methods, including Western blot, flow cytometry, messenger RNA (mRNA) sequencing, microRNA (miRNA) sequencing, and quantitative polymerase chain reaction (qPCR), we investigated the effects of USB1 deficiency on neutrophil development and differentiation, along with the underlying signaling molecular mechanisms.

Experimental results indicated that USB1 deficiency in mouse myeloid cells not only leads to dysregulation of miRNA expression but also interferes with the developmental, differentiation, and maturation processes of neutrophils by affecting key genes, such as IL1a, Selp, and Kilt. This impact can be traced back to the stages of myeloid progenitor cells.

USB1 influences neutrophil maturation and myeloid progenitor cell differentiation by regulating the expression of specific miRNAs and mRNAs. This provides novel in vivo experimental evidence for understanding the pathogenesis of PN in patients.