Piehler Armin P, Hellum Marit, Wenzel Jürgen J, Kaminski Ellen, Haug Kari Bente Foss, Kierulf Peter, Kaminski Wolfgang E
Department of Clinical Chemistry, Ulleval University Hospital, 0407 Oslo, Norway.
BMC Genomics. 2008 Apr 11;9:165. doi: 10.1186/1471-2164-9-165.
Pseudogenes are an integral component of the human genome. Little attention, however, has so far been paid to the phenomenon that some pseudogenes are transcriptionally active. Recently, we demonstrated that the human ortholog of the rodent testis-specific ATP-binding cassette (ABC) transporter Abca17 is a ubiquitously transcribed pseudogene (ABCA17P). The aim of the present study was to establish a complete inventory of all ABC transporter pseudogenes in the human genome and to identify transcriptionally active ABC transporter pseudogenes. Moreover, we tested the hypothesis that a regulatory interdependency exists between ABC transporter pseudogenes and their parental protein coding equivalents.
Systematic bioinformatic analysis revealed the existence of 22 ABC transporter pseudogenes within the human genome. We identified two clusters on chromosomes 15 and 16, respectively, which harbor almost half of all pseudogenes (n = 10). Available information from EST and mRNA databases and RT-PCR expression profiling indicate that a large portion of the ABC transporter pseudogenes (45%, n = 10) are transcriptionally active and some of them are expressed as alternative splice variants. We demonstrate that both pseudogenes of the pseudoxanthoma elasticum gene ABCC6, ABCC6P1 and ABCC6P2, are transcribed. ABCC6P1 and ABCC6 possess near-identical promoter sequences and their tissue-specific expression profiles are strikingly similar raising the possibility that they form a gene-pseudogene dual transcription unit. Intriguingly, targeted knockdown of the transcribed pseudogene ABCC6P1 resulted in a significant reduction of ABCC6 mRNA expression levels.
The human genome contains a surprisingly small number of ABC transporter pseudogenes relative to other known gene families. They are unevenly distributed across the chromosomes. Importantly, a significant portion of the ABC transporter pseudogenes is transcriptionally active. The downregulation of ABCC6 mRNA levels by targeted suppression of the expression of its pseudogene ABCC6P1 provides evidence, for the first time, for a regulatory interdependence of a transcribed pseudogene and its protein coding counterpart in the human genome.
假基因是人类基因组的一个重要组成部分。然而，迄今为止，一些假基因具有转录活性这一现象很少受到关注。最近，我们证明啮齿动物睾丸特异性ATP结合盒（ABC）转运蛋白Abca17的人类直系同源物是一个广泛转录的假基因（ABCA17P）。本研究的目的是建立人类基因组中所有ABC转运蛋白假基因的完整清单，并鉴定具有转录活性的ABC转运蛋白假基因。此外，我们检验了一个假设，即ABC转运蛋白假基因与其亲本蛋白质编码对应物之间存在调控相互依赖性。
系统的生物信息学分析揭示了人类基因组中存在22个ABC转运蛋白假基因。我们分别在15号和16号染色体上鉴定出两个簇，它们包含了几乎一半的假基因（n = 10）。来自EST和mRNA数据库的现有信息以及RT-PCR表达谱分析表明，很大一部分ABC转运蛋白假基因（45%，n = 10）具有转录活性，其中一些以可变剪接变体的形式表达。我们证明弹性假黄瘤基因ABCC6的两个假基因ABCC6P1和ABCC6P2都被转录。ABCC6P1和ABCC6具有近乎相同的启动子序列，并且它们的组织特异性表达谱惊人地相似，这增加了它们形成基因-假基因双转录单元的可能性。有趣的是，对转录的假基因ABCC6P1进行靶向敲低导致ABCC6 mRNA表达水平显著降低。
相对于其他已知基因家族，人类基因组中ABC转运蛋白假基因的数量惊人地少。它们在染色体上分布不均。重要的是，很大一部分ABC转运蛋白假基因具有转录活性。通过靶向抑制其假基因ABCC6P1的表达来下调ABCC6 mRNA水平，首次为人类基因组中一个转录假基因与其蛋白质编码对应物之间的调控相互依赖性提供了证据。
