Hu Tianxiang, Pi Wenhu, Zhu Xingguo, Yu Miao, Ha Hongseok, Shi Huidong, Choi Jeong-Hyeon, Tuan Dorothy
Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA.
Cancer Center, Augusta University, Augusta, GA 30912, USA.
Nucleic Acids Res. 2017 May 5;45(8):4479-4492. doi: 10.1093/nar/gkx055.
LTR retrotransposons are repetitive DNA elements comprising ∼10% of the human genome. However, LTR sequences are disproportionately present in human long, non-coding RNAs (lncRNAs). Whether and how the LTR lncRNAs serve biological functions are largely unknown. Here we show that in primary human erythroblasts, lncRNAs transcribed from the LTR retrotransposons of ERV-9 human endogenous retrovirus activated transcription of key erythroid genes and modulated ex vivo erythropoiesis. To dissect the functional mechanism of ERV-9 lncRNAs, we performed genome-wide RNA and ChIRP analyses before and after global knockdown or locus-specific deletion of ERV-9 lncRNAs in human erythroblasts carrying ∼4000 copies of the ERV-9 LTRs and in transgenic mouse erythroblasts carrying a single copy of the primate-specific ERV-9 LTR in the 100 kb human β-globin gene locus. We found that ERV-9 lncRNAs acted in cis to stabilize assembly of the ERV-9 LTR enhancer complex and facilitate long-range LTR enhancer function in activating transcription of downstream, cis-linked globin genes. Our findings suggested that LTR lncRNAs transcribed from many of the 4000 copies of ERV-9 LTR retrotransposons acted by a similar cis mechanism to modulate LTR enhancer function in activating transcription of downstream genes critical to cellular processes including erythropoiesis.
LTR逆转录转座子是重复DNA元件，占人类基因组的10%左右。然而，LTR序列在人类长链非编码RNA（lncRNA）中所占比例过高。LTR lncRNA是否以及如何发挥生物学功能在很大程度上尚不清楚。在这里，我们表明，在原代人类成红细胞中，从ERV-9人类内源性逆转录病毒的LTR逆转录转座子转录而来的lncRNA激活关键红系基因的转录，并调节体外红细胞生成。为了剖析ERV-9 lncRNA的功能机制，我们在携带约4000个ERV-9 LTR拷贝的人类成红细胞以及在100 kb人类β-珠蛋白基因座中携带单个灵长类特异性ERV-9 LTR拷贝的转基因小鼠成红细胞中，对ERV-9 lncRNA进行全基因组敲低或基因座特异性缺失前后，进行了全基因组RNA和ChIRP分析。我们发现，ERV-9 lncRNA以顺式作用来稳定ERV-9 LTR增强子复合物的组装，并促进长距离LTR增强子在激活下游顺式连接的珠蛋白基因转录中的功能。我们的研究结果表明，从4000个ERV-9 LTR逆转录转座子拷贝中的许多拷贝转录而来的LTR lncRNA通过类似的顺式机制发挥作用，以调节LTR增强子功能，从而激活对包括红细胞生成在内的细胞过程至关重要的下游基因的转录。
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