Lee C-C, Tsai Y-T, Kao C-W, Lee L-W, Lai H-J, Ma T-H, Chang Y-S, Yeh N-H, Lo S J
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan.
1] Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan [2] Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
Cell Death Dis. 2014 Apr 10;5(4):e1158. doi: 10.1038/cddis.2014.114.
Human diseases of impaired ribosome biogenesis resulting from disruption of rRNA biosynthesis or loss of ribosomal components are collectively described as 'ribosomopathies'. Treacher Collins syndrome (TCS), a representative human ribosomopathy with craniofacial abnormalities, is attributed to mutations in the tcof1 gene that has a homologous gene called nopp140. Previous studies demonstrated that the dao-5 (dauer and aged animal overexpression gene 5) of Caenorhabditis elegans is a member of nopp140 gene family and plays a role in nucleogenesis in the early embryo. Here, we established a C. elegans model for studying Nopp140-associated ribosomopathy. A null dao-5 mutant ok542 with a semi-infertile phenotype showed a delay in gonadogenesis, as well as a higher incidence of germline apoptosis. These phenotypes in dao-5(ok542) are likely resulted from inefficient rDNA transcription that was observed by run-on analyses and chromatin immunoprecipitation (ChIP) assays measuring the RNA Pol I occupancy on the rDNA promoter. ChIP assays further showed that the modifications of acetylated histone 4 (H4Ac) and dimethylation at the lysine 9 of histone 3 (H3K9me2) around the rDNA promoter were altered in dao-5 mutants compared with the N2 wild type. In addition, activated CEP-1 (a C. elegans p53 homolog) activity was also linked to the loss of DAO-5 in terms of the transcriptional upregulation of two CEP-1 downstream effectors, EGL-1 and CED-13. We propose that the dao-5 mutant of C. elegans can be a valuable model for studying human Nopp140-associated ribosomopathy at the cellular and molecular levels.
由于rRNA生物合成中断或核糖体成分缺失导致核糖体生物合成受损的人类疾病被统称为“核糖体病”。特雷彻·柯林斯综合征（TCS）是一种具有颅面异常的典型人类核糖体病，归因于tcof1基因突变，该基因有一个名为nopp140的同源基因。先前的研究表明，秀丽隐杆线虫的dao-5（ dauer和衰老动物过表达基因5）是nopp140基因家族的成员，在早期胚胎的核生成中发挥作用。在此，我们建立了一个用于研究与Nopp140相关的核糖体病的秀丽隐杆线虫模型。具有半不育表型的dao-5无效突变体ok542表现出性腺发育延迟，以及生殖细胞凋亡发生率更高。dao-5(ok542)中的这些表型可能是由于通过连续分析和染色质免疫沉淀（ChIP）测定法观察到的rDNA转录效率低下所致，ChIP测定法测量了RNA聚合酶I在rDNA启动子上的占有率。ChIP测定法进一步表明，与N2野生型相比，dao-5突变体中rDNA启动子周围的乙酰化组蛋白4（H4Ac）修饰和组蛋白3赖氨酸9（H3K9me2）的二甲基化发生了改变。此外，就两个CEP-1下游效应器EGL-1和CED-13的转录上调而言，活化的CEP-1（秀丽隐杆线虫p53同源物）活性也与DAO-5的缺失有关。我们提出，秀丽隐杆线虫的dao-5突变体可以作为在细胞和分子水平上研究人类与Nopp140相关的核糖体病的有价值模型。
