Pi Wenhu, Yang Zhongan, Wang Jian, Ruan Ling, Yu Xiuping, Ling Jianhua, Krantz Sanford, Isales Carlos, Conway Simon J, Lin Shuo, Tuan Dorothy
Department of Biochemistry and Molecular Biology and Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA.
Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):805-10. doi: 10.1073/pnas.0307698100. Epub 2004 Jan 12.
The solitary LTRs of ERV-9 human endogenous retrovirus are middle repetitive DNAs associated with 3,000-4,000 human gene loci including the beta-globin gene locus where the ERV-9 LTR is juxtaposed to the locus control region (beta-LCR) far upstream of the globin genes. The ERV-9 LTRs are conserved during primate evolution, but their function in the primate genomes is unknown. Here, we show that in transgenic zebrafish harboring the beta-globin ERV-9 LTR coupled to the GFP gene, the LTR enhancer was active and initiated synthesis of GFP mRNA in oocytes but not in spermatozoa, and GFP expression in the embryos was maternally inherited. The LTR enhancer was active also in stem/progenitor cell regions of adult tissues of transgenic zebrafish. In human tissues, ERV-9 LTR enhancer was active also in oocytes and stem/progenitor cells but not in spermatozoa and a number of differentiated, adult somatic cells. Transcriptional analyses of the human beta-globin gene locus showed that the beta-globin ERV-9 LTR enhancer initiated RNA synthesis from the LTR in the direction of the downstream beta locus control region and globin genes in ovary and erythroid progenitor cells. The findings suggest that, during oogenesis, ERV-9 LTR enhancers in the human genome could activate the cis-linked gene loci to synthesize maternal mRNAs required for early embryogenesis. Alternatively, the ERV-9 LTR enhancers, in initiating RNA syntheses into the downstream genomic DNAs, could transcriptionally potentiate and preset chromatin structure of the cis-linked gene loci in oocytes and adult stem/progenitor cells.
ERV-9人类内源性逆转录病毒的单个长末端重复序列（LTR）是中等重复DNA，与3000 - 4000个人类基因座相关，包括β-珠蛋白基因座，其中ERV-9 LTR与位于珠蛋白基因上游远处的基因座控制区（β-LCR）并列。ERV-9 LTR在灵长类动物进化过程中是保守的，但其在灵长类动物基因组中的功能尚不清楚。在这里，我们表明，在携带与绿色荧光蛋白（GFP）基因偶联的β-珠蛋白ERV-9 LTR的转基因斑马鱼中，LTR增强子具有活性，并在卵母细胞中启动GFP mRNA的合成，但在精子中不启动，并且胚胎中的GFP表达是母系遗传的。LTR增强子在转基因斑马鱼成体组织的干细胞/祖细胞区域也具有活性。在人类组织中，ERV-9 LTR增强子在卵母细胞和干细胞/祖细胞中也具有活性，但在精子和许多分化的成体体细胞中不具有活性。对人类β-珠蛋白基因座的转录分析表明，β-珠蛋白ERV-9 LTR增强子在卵巢和红系祖细胞中从LTR向下游β基因座控制区和珠蛋白基因的方向启动RNA合成。这些发现表明，在卵子发生过程中，人类基因组中的ERV-9 LTR增强子可以激活顺式连接的基因座，以合成早期胚胎发育所需的母体mRNA。或者，ERV-9 LTR增强子在启动RNA合成进入下游基因组DNA时，可以转录增强并预设卵母细胞和成体干细胞/祖细胞中顺式连接基因座的染色质结构。
