Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies.
Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies.
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DOI：
10.1186/s13059-015-0732-z
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发表时间：
2015-09-01
期刊：
影响因子：
12.3
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Ruzycki PA;Tran NM;Kefalov VJ;Kolesnikov AV;Chen S
视锥-视杆同源异型盒蛋白CRX的突变通常与发病年龄和严重程度不同的显性致盲性视网膜病变相关。携带不同Crx突变的五种充分表征的小鼠模型显示出广泛的疾病表型。为了确定表型变异性是否与CRX靶基因表达的不同变化相关，我们对其中三个模型进行了RNA-seq分析，并将结果与已发表的数据进行了比较。尽管所测试的三种模型之间存在显著的表型差异，但检测到共享基因组中的分级表达变化。表型严重程度与编码关键视杆细胞和视锥细胞光转导蛋白的基因的下调相关。有趣的是，在越来越严重的小鼠模型中，许多杆富集基因的转录递减，而锥富集基因的转录递增。与在正常视网膜中显示出高度CRX结合和动态表观遗传特征的下调基因不同，上调的视锥富集基因与CRX的直接活性无关，而是可能反映了视杆细胞命运完整性的变化。此外，这些分析描述了微小基因表达变化对表型的影响，因为两种突变体显示出略微可区分的表达模式，但存在巨大的表型差异，包括视网膜变性的不同机制。我们的研究结果暗示了基因表达水平对感光细胞功能和存活的阈值效应，突出了CRX在感光细胞亚型发育和维持中的重要性，并为CRX相关视网膜病变的表型变异提供了分子基础。本文的在线版本（doi：10.1186/s13059-015-0732-z）包含补充材料，可供授权用户使用。
Mutations in the cone-rod-homeobox protein CRX are typically associated with dominant blinding retinopathies with variable age of onset and severity. Five well-characterized mouse models carrying different Crx mutations show a wide range of disease phenotypes. To determine if the phenotype variability correlates with distinct changes in CRX target gene expression, we perform RNA-seq analyses on three of these models and compare the results with published data. Despite dramatic phenotypic differences between the three models tested, graded expression changes in shared sets of genes are detected. Phenotype severity correlates with the down-regulation of genes encoding key rod and cone phototransduction proteins. Interestingly, in increasingly severe mouse models, the transcription of many rod-enriched genes decreases decrementally, whereas that of cone-enriched genes increases incrementally. Unlike down-regulated genes, which show a high degree of CRX binding and dynamic epigenetic profiles in normal retinas, the up-regulated cone-enriched genes do not correlate with direct activity of CRX, but instead likely reflect a change in rod cell-fate integrity. Furthermore, these analyses describe the impact of minor gene expression changes on the phenotype, as two mutants showed marginally distinguishable expression patterns but huge phenotypic differences, including distinct mechanisms of retinal degeneration. Our results implicate a threshold effect of gene expression level on photoreceptor function and survival, highlight the importance of CRX in photoreceptor subtype development and maintenance, and provide a molecular basis for phenotype variability in CRX-associated retinopathies. The online version of this article (doi:10.1186/s13059-015-0732-z) contains supplementary material, which is available to authorized users.