Loss of Dnajc21 leads to cytopenia and altered nucleotide metabolism in zebrafish
Mutations in the DNAJC21 gene were recently described in Shwachman-Diamond syndrome (SDS), a bone marrow failure syndrome with high predisposition for myeloid malignancies. To study the underlying biology in hematopoiesis regulation and disease, we generated the first in vivo model of Dnajc21 deficiency using zebrafish. Zebrafish dnajc21 mutants phenocopy key SDS patient phenotypes such as cytopenia, reduced growth and defective ribosome biogenesis. We show that cytopenia results from impaired hematopoietic differentiation and cell proliferation, and is accompanied by an expansion of hematopoietic stem and progenitor cells during both embryonic and adult hematopoiesis. The introduction of a tp53 point mutation in the dnajc21 mutants results in myelodysplastic syndrome with erythroid dysplasia as early as four months of age. Using transcriptomic and metabolomic analyses, we show that Dnajc21 regulates various metabolic pathways including nucleotide biosynthesis. Chemical modulation of the pyrimidine biosynthesis pathway in dnajc21 mutants reveals an association with neutrophil differentiation, suggesting a novel mechanism in dnajc21-mutant SDS biology. Overall design: Gene expression profiling through RNA sequencing of wildtype and dnajc21 mutant zebrafish at 48 hours post-fertilization (hpf)