Abstract
Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome that is characterized by pure red-cell aplasia and associated physical deformities. It has been proven that defects of ribosomal proteins can lead to this disease and that RPS19 is the most frequently mutated gene in DBA patients. Previous studies suggest that p53-dependent genes and pathways play important roles in RPS19-deficient embryos. However, whether there are other vital factors linked to DBA has not been fully clarified. In this study, we compared the whole genome RNA-Seq data of zebrafish embryos injected with RPS19 morpholino (RPS19 MO), RPS19 and p53 morpholino simultaneously (RPS19+p53 MO) and control morpholino (control). We found that genes enriched in the functions of hematological systems, nervous system development and skeletal and muscular disorders had significant differential expression in RPS19 MO embryos compared with controls. Co-inhibition of p53 partially alleviates the abnormalities for RPS19-deficient embryos. However, the hematopoietic genes, which were down-regulated significantly in RPS19 MO embryos, were not completely recovered by the co-inhibition of p53. Furthermore, we identified the genome-wide p53-dependent and -independent genes and pathways. These results indicate that not only p53 family members but also other factors have important impacts on RPS19-deficient embryos. The detection of potential pathogenic genes and pathways provides us a new paradigm for future research on DBA, which is a systematic and complex hereditary disease.
Highlights
Diamond-Blackfan anemia (DBA) is a congenital anemia and broad developmental disease that develops soon after birth
The anemia results from a failure of erythropoiesis, with normal platelet and myeloid lineages, and it can be managed with steroids, blood transfusions, or stem cell transplantation [1]
We identified genes that their expression levels were reversed in embryos co-injected with RPS19 MO+p53 MO, and defined them as p53 dependent genes
Summary
Diamond-Blackfan anemia (DBA) is a congenital anemia and broad developmental disease that develops soon after birth. The anemia results from a failure of erythropoiesis, with normal platelet and myeloid lineages, and it can be managed with steroids, blood transfusions, or stem cell transplantation [1]. DBA is the first known inherited disease that results from a defect in a structural ribosomal protein [2]. Mutations in an increasing number of genes encoding RPs of the small (RPS19, RPS24, RPS17, RPS7, RPS10, RPS26) and large (RPL35A, RPL5, RPL11) ribosomal subunits have been shown to cause DBA. RPS19 is the most frequently mutated ribosomal protein gene, which accounts for approximately 25% of DBA patients [3]. How the ribosomal protein mutations affect hematopoiesis is still unclear
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