Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the Frog Xenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type.
Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the Frog Xenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type.
复制标题
非洲爪蟾旁系同源芳基烃受体的亚功能化：不同的靶基因和单细胞类型中对特定激动剂的差异反应。
DOI：
10.1093/toxsci/kfw212
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Powell,WadeH
中科院分区：
文献类型：
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作者：
Freeburg,ScottH;Engelbrecht,Eric;Powell,WadeH
基因复制带来了遗传冗余，可以促进子功能化，即祖先功能在旁系同源物之间的划分。我们利用非洲爪蛙（Xenopus laevis）最近的基因组复制来探究芳烃受体（AHR）等位基因之间可能的功能差异，AHR是一种配体激活的转录因子，介导二恶英类化合物的毒性，并在脊椎动物心血管、肝脏和免疫系统的生理和发育中发挥作用。 laevisha有2个AHR基因，AHR1α和AHR1β。为了检验编码蛋白表现出不同分子功能的假设，我们在 XLK-WG 细胞中使用 TALEN，生成缺乏每个 AHR 功能版本的突变株系，并测量多个靶基因对有毒异生物质 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 和候选内源配体 6-甲酰基吲哚并[3,2-b]咔唑 (FICZ) 的转录反应性。尽管野生型细胞中 AHR1β 的丰度要低得多，但 AHR1α 或 AHR1β 的突变使经典 AHR 靶标细胞色素 P4501A6 的 TCDD 诱导减少了 75%。更适度诱导的靶基因，编码芳基碳氢化合物受体阻遏物 (AHRR)、含有血影蛋白重复的核膜蛋白 1 (SYNE-1) 和间隙连接蛋白 γ 1 (GJC1)，仅受 AHR1α 调节。 AHR1β负责FICZ对CYP1A6的诱导，而AHR1α介导FICZ对AHRR的诱导。我们得出的结论是，即使在单一细胞类型中，AHR1α 和 AHR1β 也具有响应特定激动剂的不同转录功能。青蛙 AHR 旁系同源物的功能分析促进了对 AHR 进化的理解以及发育毒理学青蛙模型（如 FETAX）的使用。
Gene duplication confers genetic redundancy that can facilitate subfunctionalization, the partitioning of ancestral functions between paralogs. We capitalize on a recent genome duplication inXenopus laevis(African clawed frog) to interrogate possible functional differentiation between alloalleles of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates toxicity of dioxin-like compounds and plays a role in the physiology and development of the cardiovascular, hepatic, and immune systems in vertebrates.X. laevishas 2AHRgenes,AHR1αandAHR1β. To test the hypothesis that the encoded proteins exhibit different molecular functions, we used TALENs in XLK-WG cells, generating mutant lines lacking functional versions of each AHR and measuring the transcriptional responsiveness of several target genes to the toxic xenobiotic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the candidate endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). Mutation of eitherAHR1αorAHR1βreduced TCDD induction of the canonical AHR target,Cytochrome P4501A6, by 75%, despite the much lower abundance of AHR1β in wild-type cells. More modestly induced target genes, encoding aryl hydrocarbon receptor repressor (AHRR), spectrin repeat-containing nuclear envelope protein 1 (SYNE-1), and gap junction protein gamma 1 (GJC1), were regulated solely by AHR1α. AHR1β was responsible forCYP1A6induction by FICZ, while AHR1α mediated FICZ induction ofAHRR. We conclude that AHR1α and AHR1β have distinct transcriptional functions in response to specific agonists, even within a single cell type. Functional analysis of frog AHR paralogs advances the understanding of AHR evolution and as well as the use of frog models of developmental toxicology such as FETAX.