Predicting Modifiers of Genotype-Phenotype Correlations in Craniofacial Development.
Predicting Modifiers of Genotype-Phenotype Correlations in Craniofacial Development.
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DOI：
10.3390/ijms24021222
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发表时间：
2023-01-08
影响因子：
5.6
通讯作者：
Eberhart, Johann K.
中科院分区：
文献类型：
--
作者：
Kar, Ranjeet D.;Eberhart, Johann K.
大多数人类出生缺陷即使具有共同的遗传基础，在表型上也存在差异。我们对这种变异机制的理解是有限的，但它们被认为是由于复杂的基因-环境相互作用造成的。转录因子 Gata3 的缺失与高度变异的人类出生缺陷 HDR 综合征和身材矮小症有关，并可能导致神经嵴衍生的面部骨骼的破坏。我们已经证明，斑马鱼 gata3 突变体模拟了人类中所见的变异性，其遗传背景和候选途径改变了最终的表型。在这项研究中，我们试图使用公正的生物信息学方法来识别 gata3 突变颅面表型的环境调节剂。 LINCs L1000 数据集可识别产生与输入基因列表呈正相关或负相关的差异基因表达的化学物质。预计这些化学物质将分别恶化或减轻突变表型。我们对从对照组、Gata3 功能丧失组和 Gata3 救援组中分离的斑马鱼神经嵴细胞进行了 RNA 测序。差异表达分析揭示了 gata3 的 551 个潜在靶标。我们查询了 LINCs 数据库，其中包含 100 个最上调和 100 个最下调基因。我们测试了预计会使突变表型恶化的前八种可用化学物质，以及预测会减轻表型的前八种化学物质。其中，我们发现长春碱（一种微管抑制剂）和氯贝酸（一种 PPAR-α 激动剂）确实会使 gata3 表型恶化。拓扑异构酶 II 和 RNA-pol II 抑制剂柔红霉素和雷公藤甲素分别减轻了表型。 GO 分析发现我们的 RNA-seq 数据中丰富了 Wnt 信号传导和 RNA 聚合酶功能，这与某些化学物质的作用机制一致。我们的研究阐明了 Gata3 功能的多种潜在途径，并展示了识别基因型-表型相关性修饰因子的系统、公正的过程。
Most human birth defects are phenotypically variable even when they share a common genetic basis. Our understanding of the mechanisms of this variation is limited, but they are thought to be due to complex gene-environment interactions. Loss of the transcription factor Gata3 associates with the highly variable human birth defects HDR syndrome and microsomia, and can lead to disruption of the neural crest-derived facial skeleton. We have demonstrated that zebrafish gata3 mutants model the variability seen in humans, with genetic background and candidate pathways modifying the resulting phenotype. In this study, we sought to use an unbiased bioinformatic approach to identify environmental modifiers of gata3 mutant craniofacial phenotypes. The LINCs L1000 dataset identifies chemicals that generate differential gene expression that either positively or negatively correlates with an input gene list. These chemicals are predicted to worsen or lessen the mutant phenotype, respectively. We performed RNA-seq on neural crest cells isolated from zebrafish across control, Gata3 loss-of-function, and Gata3 rescue groups. Differential expression analyses revealed 551 potential targets of gata3. We queried the LINCs database with the 100 most upregulated and 100 most downregulated genes. We tested the top eight available chemicals predicted to worsen the mutant phenotype and the top eight predicted to lessen the phenotype. Of these, we found that vinblastine, a microtubule inhibitor, and clofibric acid, a PPAR-alpha agonist, did indeed worsen the gata3 phenotype. The Topoisomerase II and RNA-pol II inhibitors daunorubicin and triptolide, respectively, lessened the phenotype. GO analysis identified Wnt signaling and RNA polymerase function as being enriched in our RNA-seq data, consistent with the mechanism of action of some of the chemicals. Our study illustrates multiple potential pathways for Gata3 function, and demonstrates a systematic, unbiased process to identify modifiers of genotype-phenotype correlations.
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影响因子：
--
作者：
Fukuda Y;Sano O;Kazetani K;Yamamoto K;Iwata H;Matsui J
通讯作者：
Matsui J
DOI：
10.1083/jcb.200309096
发表时间：
2004-01-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
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Salinas PC
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作者：
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通讯作者：
Oezbek, Suat
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作者：
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通讯作者：
Liao, Eric C.
影响因子：
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作者：
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通讯作者：
Liao, Eric C.