Mutation of a Nopp140 gene dao-5 alters rDNA transcription and increases germ cell apoptosis in C. elegans.
Mutation of a Nopp140 gene dao-5 alters rDNA transcription and increases germ cell apoptosis in C. elegans.
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DOI：
10.1038/cddis.2014.114
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发表时间：
2014-04-10
影响因子：
9
通讯作者：
Lo SJ
中科院分区：
文献类型：
--
作者：
Lee CC;Tsai YT;Kao CW;Lee LW;Lai HJ;Ma TH;Chang YS;Yeh NH;Lo SJ
由于rRNA生物合成中断或核糖体成分丢失而导致的人类核糖体生物发生障碍的疾病统称为核糖病。Treacher Collins综合征(TCS)是一种具有颅面部异常的典型人类核糖体病，其原因是TCOF1基因突变，该基因具有称为nopp140的同源基因。以往的研究表明，秀丽线虫的dao-5基因(Dauer and老年动物过表达基因5)是nopp140基因家族的成员，在早期胚胎的核发生中发挥作用。在这里，我们建立了一个研究Nopp140相关核糖体病的线虫模型。具有半不育表型的空DAO-5突变体ok542显示性腺发生延迟，以及生殖系细胞凋亡的发生率较高。Dao-5(Ok542)的这些表型可能是由于rDNA转录效率低下所致，这是通过连续分析和染色质免疫沉淀(ChIP)法检测rDNA启动子上RNAPol I占有率的方法观察到的。芯片分析进一步表明，与野生型相比，Dao-5突变体中组蛋白4(H4Ac)的乙酰化修饰和组蛋白3(H3K9me2)在rDNA启动子周围的9位赖氨酸的二甲基化发生了改变。此外，激活的CEP-1(线虫P53同源物)活性也与DAO-5的缺失有关，这是因为CEP-1下游的两个效应物EGL-1和CED-13转录上调。我们认为，线虫Dao-5突变体可以成为在细胞和分子水平上研究人类Nopp140相关核糖体病的有价值的模型。
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.