Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, China.
PLoS One. 2013 Aug 19;8(8):e71782. doi: 10.1371/journal.pone.0071782. eCollection 2013.
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.
Diamond-Blackfan 贫血（DBA）是一种罕见的遗传性骨髓衰竭综合征，其特征为纯红细胞再生障碍和相关的身体畸形。已经证明核糖体蛋白的缺陷可导致这种疾病，并且 RPS19 是 DBA 患者中最常突变的基因。先前的研究表明，p53 依赖性基因和途径在 RPS19 缺陷型胚胎中发挥重要作用。然而，是否存在与 DBA 相关的其他重要因素尚未完全阐明。在这项研究中，我们比较了注射 RPS19 形态发生素（RPS19 MO）、RPS19 和 p53 形态发生素同时（RPS19+p53 MO）和对照形态发生素（对照）的斑马鱼胚胎的全基因组 RNA-Seq 数据。我们发现，与对照相比，在 RPS19 MO 胚胎中富集在造血系统、神经系统发育和骨骼和肌肉疾病功能的基因具有显著的差异表达。p53 的共抑制部分缓解了 RPS19 缺陷型胚胎的异常。然而，在 RPS19 MO 胚胎中显著下调的造血基因并未被 p53 的共抑制完全恢复。此外，我们鉴定了全基因组范围内 p53 依赖性和非依赖性基因和途径。这些结果表明，不仅 p53 家族成员，而且其他因素对 RPS19 缺陷型胚胎有重要影响。潜在致病基因和途径的检测为我们未来对 DBA 的研究提供了一个新的范例，DBA 是一种系统性和复杂性的遗传性疾病。
