Abstract
BackgroundDiamond–Blackfan anemia (DBA) is a class of human diseases linked to defective ribosome biogenesis that results in clinical phenotypes. Genetic mutations in ribosome protein (RP) genes lead to DBA phenotypes, including hematopoietic defects and physical deformities. However, little is known about the global regulatory network as well as key miRNAs and gene pathways in the zebrafish model of DBA.ResultsIn this study, we establish the DBA model in zebrafish using an RPS24 morpholino and found that RPS24 is required for both primitive hematopoiesis and definitive hematopoiesis processes that are partially mediated by the p53 pathway. Several deregulated genes and miRNAs were found to be related to hematopoiesis, vascular development and apoptosis in RPS24-deficient zebrafish via RNA-seq and miRNA-seq data analysis, and a comprehensive regulatory network was first constructed to identify the mechanisms of key miRNAs and gene pathways in the model. Interestingly, we found that the central node genes in the network were almost all targeted by significantly deregulated miRNAs. Furthermore, the enforced expression of miR-142-3p, a uniquely expressed miRNA, causes a significant decrease in primitive erythrocyte progenitor cells and HSCs.ConclusionsThe present analyses demonstrate that the comprehensive regulatory network we constructed is useful for the functional prediction of new and important miRNAs in DBA and will provide insights into the pathogenesis of mutant rps24-mediated human DBA disease.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-759) contains supplementary material, which is available to authorized users.
Highlights
Diamond–Blackfan anemia (DBA) is a class of human diseases linked to defective ribosome biogenesis that results in clinical phenotypes
The embryos injected with control Morpholino knockdown (MO) did not display any morphological changes; the Ribosomal protein S24 (RPS24) MO exhibited various phenotypes, including tail deformities and hematopoietic defects
The hemoglobin staining results indicated that hemoglobin-stained blood cells were markedly decreased in RPS24 MO at 48 hpf and were partially rescued in RPS24 + p53 MO embryos (Figure 1), similar to our previous RPS19 MO and RPL11 MO phenotypes [18]
Summary
Diamond–Blackfan anemia (DBA) is a class of human diseases linked to defective ribosome biogenesis that results in clinical phenotypes. RPL11 mutations lead to a dramatic decrease in progenitor cell proliferation, delayed erythroid differentiation, with a marked increase in apoptosis and G0/G1 cell cycle arrest, and activation of the p53 pathway [11]. The exact mechanism of DBA may be a combined effect of ribosome synthesis and p53 activation, and more efforts are needed to correlate specific mutations to the disease phenotypes such as its impact on erythropoiesis. To achieve this goal, the regulatory networks for each RP mutation may be needed to be established for careful examination and comparison. Unbiased screen approaches are necessary to understand DBA pathogenesis using various models, such as mouse and zebrafish, in addition to patient samples because no mutations were found in approximately 50% of clinically diagnosed DBA patients
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