Multipotent genetic suppression of retrotransposon-induced mutations by Nxf1 through fine-tuning of alternative splicing.
Multipotent genetic suppression of retrotransposon-induced mutations by Nxf1 through fine-tuning of alternative splicing.
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DOI：
10.1371/journal.pgen.1000484
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发表时间：
2009-05
期刊：
影响因子：
4.5
通讯作者：
Hamilton BA
中科院分区：
文献类型：
--
作者：
Concepcion D;Flores-García L;Hamilton BA
细胞基因表达机制与分子寄生虫（如病毒和转座子）共同进化，这些分子寄生虫依赖宿主细胞进行表达和繁殖。我们以前报道，野生型小鼠Nxf1（抽头），宿主mRNA核输出机制的关键组成部分，等位基因抑制两个内源性逆转录病毒诱导的突变，并显示积极选择的暗示性证据。在这里，我们表明，Nxf1CAST抑制特定的和频繁的一类脑池内A颗粒（IAP）诱导的突变，包括Ap3d1mh2J，Hermansky-Pudlak综合征的模型，和Atcayhes，开曼共济失调的orthopathic基因模型，等等。抑制的分子表型包括正确剪接的mRNA水平增加两倍，以及从插入的等位基因积累的突变体特异性、交替加工的RNA减少。涉及ETn和LINE元件的插入突变不受抑制，表明这种抑制机制具有高度特异性。这些结果暗示Nxf1在前mRNA加工的某些情况下，证明了Nxf1CAST等位基因用于操纵现有小鼠疾病模型的有用范围，并特别暗示了Cayman共济失调治疗益处的低功能阈值。逆转录病毒和转座因子是整合到宿主基因组中的分子寄生虫，需要宿主细胞机制进行基因表达、复制和传播。整合元件可以通过转录和转录后机制改变附近宿主基因的表达。宿主细胞机制的组成部分，可以适应有利于宿主细胞的遗传程序超过寄生虫的遗传程序，可以提供一个水平的先天免疫。在实验室小鼠中，内源性逆转录病毒是病毒衍生的移动的元件，其导致许多自发突变。一个常见的类别涉及反转录转座到转录有义方向的基因内含子中，这改变了宿主基因前mRNA剪接。在这里，我们表明，对于内源性逆转录病毒的脑池内A颗粒（IAP）家族，在野生亚洲小鼠（小家鼠）中发现的典型mRNA输出因子Nxf1的等位基因抑制大多数插入这一类（七个测试六）。据我们所知，这些结果使Nxf1的最广泛的相互作用的修饰基因尚未记录在这个研究充分的物种。这些结果对操纵小鼠疾病模型中的基因表达、Nxf1在前mRNA加工中的作用以及Cayman共济失调治疗干预的动态范围具有重要意义。
Cellular gene expression machinery has coevolved with molecular parasites, such as viruses and transposons, which rely on host cells for their expression and reproduction. We previously reported that a wild-derived allele of mouse Nxf1 (Tap), a key component of the host mRNA nuclear export machinery, suppresses two endogenous retrovirus-induced mutations and shows suggestive evidence of positive selection. Here we show that Nxf1CAST suppresses a specific and frequent class of intracisternal A particle (IAP)-induced mutations, including Ap3d1mh2J, a model for Hermansky-Pudlak syndrome, and Atcayhes, an orthologous gene model for Cayman ataxia, among others. The molecular phenotype of suppression includes ∼two-fold increase in the level of correctly-spliced mRNA and a decrease in mutant-specific, alternatively-processed RNA accumulating from the inserted allele. Insertional mutations involving ETn and LINE elements are not suppressed, demonstrating a high degree of specificity to this suppression mechanism. These results implicate Nxf1 in some instances of pre-mRNA processing, demonstrate the useful range of Nxf1CAST alleles for manipulating existing mouse models of disease, and specifically imply a low functional threshold for therapeutic benefit in Cayman ataxia. Retroviruses and transposable elements are molecular parasites that integrate into the host genome and require host cell machinery for gene expression, replication and dissemination. Integrating elements can alter the expression of nearby host genes through both transcriptional and post-transcriptional mechanisms. Components of the host cell machinery that can adapt to favor genetic programs of the host cell over those of the parasite may afford one level of innate immunity. In laboratory mice, endogenous retroviruses are virus-derived mobile elements that account for many spontaneous mutations. A frequent class involves retrotransposition into introns of genes in the transcriptional sense orientation, which alters host gene pre-mRNA splicing. Here we show that for the intracisternal A particle (IAP) family of endogenous retroviruses, an allele of the canonical mRNA export factor Nxf1 found in wild Asiatic mice (Mus musculus castaneus) suppresses most insertions of this class (six of seven tested). To our knowledge, these results make Nxf1 the most broadly interacting modifier gene yet documented in this well-studied species. These results have significant implications for manipulating gene expression in mouse models of disease, the role of Nxf1 in pre-mRNA processing and in the dynamic range for therapeutic intervention in Cayman ataxia.
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DOI：
10.1111/j.1600-0749.1995.tb00677.x
发表时间：
1995-12-01
期刊：
PIGMENT CELL RESEARCH
影响因子：
--
作者：
Boissy, RE;Lamoreux, ML
通讯作者：
Lamoreux, ML
影响因子：
11.4
作者：
Braun, IC;Rohrbach, E;Izaurralde, E
通讯作者：
Izaurralde, E
影响因子：
3.3
作者：
Concepcion, D;Seburn, KL;Hamilton, BA
通讯作者：
Hamilton, BA
影响因子：
16.2
作者：
Hamilton, BA;Smith, DJ;Lander, ES
通讯作者：
Lander, ES
影响因子：
56.9
作者：
He, L;Lu, XY;Gunn, TM
通讯作者：
Gunn, TM