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L1反转录转座子引起的转录干扰及其对哺乳动物转录组的影响。

Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes.

作者信息

Han Jeffrey S, Szak Suzanne T, Boeke Jef D

机构信息

Department of Molecular Biology and Genetics and High Throughput Biology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

出版信息

Nature. 2004 May 20;429(6989):268-74. doi: 10.1038/nature02536.

Abstract

LINE-1 (L1) elements are the most abundant autonomous retrotransposons in the human genome, accounting for about 17% of human DNA. The L1 retrotransposon encodes two proteins, open reading frame (ORF)1 and the ORF2 endonuclease/reverse transcriptase. L1 RNA and ORF2 protein are difficult to detect in mammalian cells, even in the context of overexpression systems. Here we show that inserting L1 sequences on a transcript significantly decreases RNA expression and therefore protein expression. This decreased RNA concentration does not result from major effects on the transcription initiation rate or RNA stability. Rather, the poor L1 expression is primarily due to inadequate transcriptional elongation. Because L1 is an abundant and broadly distributed mobile element, the inhibition of transcriptional elongation by L1 might profoundly affect expression of endogenous human genes. We propose a model in which L1 affects gene expression genome-wide by acting as a 'molecular rheostat' of target genes. Bioinformatic data are consistent with the hypothesis that L1 can serve as an evolutionary fine-tuner of the human transcriptome.

摘要

LINE-1(L1)元件是人类基因组中最丰富的自主逆转座子,约占人类DNA的17%。L1逆转座子编码两种蛋白质,开放阅读框(ORF)1和ORF2核酸内切酶/逆转录酶。即使在过表达系统的情况下,L1 RNA和ORF2蛋白在哺乳动物细胞中也很难检测到。在这里,我们表明在转录本上插入L1序列会显著降低RNA表达,进而降低蛋白质表达。RNA浓度的降低并非主要源于对转录起始速率或RNA稳定性的重大影响。相反,L1表达不佳主要是由于转录延伸不足。由于L1是一种丰富且广泛分布的移动元件,L1对转录延伸的抑制可能会深刻影响人类内源性基因的表达。我们提出了一个模型,其中L1通过充当靶基因的“分子变阻器”在全基因组范围内影响基因表达。生物信息学数据与L1可作为人类转录组进化微调器的假设一致。

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