The Opitz syndrome gene Mid1 is transcribed from a human endogenous retroviral promoter
The Opitz syndrome gene Mid1 is transcribed from a human endogenous retroviral promoter
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DOI：
10.1093/oxfordjournals.molbev.a004017
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发表时间：
2002-11-01
影响因子：
10.7
通讯作者：
Mager, DL
中科院分区：
文献类型：
--
作者：
Landry, JR;Rouhi, A;Mager, DL
人类内源性逆转录病毒 (HERV) 和其他含有长末端重复序列 (LTR) 的元件构成了人类基因组的很大一部分 (8%)，并且可能是灵长类动物进化过程中逆转录病毒感染的痕迹。人类 DNA 中存在的许多 HERV 保留了功能性启动子、增强子和多腺苷酸化信号，这些调节序列有可能改变附近基因的表达。为了识别有助于人类基因转录的逆转录病毒元件，我们筛选了嵌合（病毒细胞）转录本的序列数据库。这些搜索揭示了一个融合转录本，其中包含与 Opitz 综合征基因 Mid1 相关的 HERV-E 元件的 LTR。我们通过 cDNA 末端的 5' 快速扩增 (RACE) 证实了嵌合转录物的真实性，并确定 Mid1 mRNA 亚型是从逆转录病毒 LTR 转录而来的。逆转录病毒第一个外显子的鉴定表明 Mid1 存在替代启动子，因为之前已报道过该基因的非逆转录病毒（天然）5'非翻译区 (UTR)。尽管在所有测试的组织中都可以检测到 Mid1 转录本，但定量实时逆转录聚合酶链反应表明，逆转录病毒启动子对胎盘和胚胎肾中 Mid1 转录本的水平有显着贡献，其中嵌合 mRNA 分别占总体 Mid1 mRNA 的 25% 和 22%。瞬时转染研究支持LTR在胎盘和胚胎肾细胞系中作为强组织特异性启动子的作用，并表明LTR作为增强子的功能。这些发现提供了进一步的证据，表明一些内源性逆转录病毒通过向细胞基因提供转录调控元件而进化出了生物学功能。
Human endogenous retroviruses (HERVs) and other long terminal repeat (LTR)-containing elements comprise a significant portion (8%) of the human genome and are likely vestiges of retroviral infections during primate evolution. Many of the HERVs present in human DNA have retained functional promoter, enhancer, and polyadenylation signals, and these regulatory sequences have the potential to modify the expression of nearby genes. To identify retroviral elements that contribute to the transcription of human genes, we screened sequence databases for chimeric (viral-cellular) transcripts. These searches revealed a fusion transcript containing the LTR of an HERV-E element linked to the Opitz syndrome gene Mid1. We confirmed the authenticity of the chimeric transcript by 5' rapid amplification of cDNA ends (RACE) and established that the Mid1 mRNA isoform was transcribed from a retroviral LTR. The identification of a retroviral first exon suggested the existence of alternative promoters for Mid1 because nonretroviral (native) 5' untranslated regions (UTRs) had been reported previously for this gene. Although Mid1 transcripts could be detected in all tissues tested, quantitative real-time reverse transcription-polymerase chain reaction indicated that the retroviral promoter contributes significantly to the level of Mid1 transcripts in placenta and embryonic kidney, where chimeric mRNAs were found to represent 25% and 22% of overall Mid1 mRNAs, respectively. Transient transfection studies supported a role for the LTR as a strong tissue-specific promoter in placental and embryonic kidney cell lines and suggested a function for the LTR as an enhancer. These findings provide further evidence that some endogenous retroviruses have evolved a biological function by contributing transcriptional regulatory elements to cellular genes.