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首页> 外文期刊>Disease models & mechanisms: DMM >Generation of a double binary transgenic zebrafish model to study myeloid gene regulation in response to oncogene activation in melanocytes
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Generation of a double binary transgenic zebrafish model to study myeloid gene regulation in response to oncogene activation in melanocytes

机译：生成双二进制转基因斑马鱼模型以研究响应黑素细胞中致癌基因激活的髓样基因调控

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A complex network of inflammatory genes is closely linked to somatic cell transformation and malignant disease. Immune cells and their associated molecules are responsible for detecting and eliminating cancer cells as they establish themselves as the precursors of a tumour. By the time a patient has a detectable solid tumour, cancer cells have escaped the initial immune response mechanisms. Here, we describe the development of a double binary zebrafish model that enables regulatory programming of the myeloid cells as they respond to oncogene-activated melanocytes to be explored, focussing on the initial phase when cells become the precursors of cancer. A hormone-inducible binary system allows for temporal control of expression of different Ras oncogenes ( NRas Q61K, HRas G12V and KRas G12V) in melanocytes, leading to proliferation and changes in morphology of the melanocytes. This model was coupled to binary cell-specific biotagging models allowing in vivo biotinylation and subsequent isolation of macrophage or neutrophil nuclei for regulatory profiling of their active transcriptomes. Nuclear transcriptional profiling of neutrophils, performed as they respond to the earliest precursors of melanoma in vivo , revealed an intricate landscape of regulatory factors that may promote progression to melanoma, including Serpinb1l4, Fgf1, Fgf6, Cathepsin H, Galectin 1 and Galectin 3. The model presented here provides a powerful platform to study the myeloid response to the earliest precursors of melanoma.
机译：炎性基因的复杂网络与体细胞转化和恶性疾病密切相关。免疫细胞及其相关分子负责将癌细胞确立为肿瘤的前体，从而检测和消除癌细胞。当患者患有可检测的实体瘤时，癌细胞已经摆脱了最初的免疫反应机制。在这里，我们描述了双二进制斑马鱼模型的开发，该模型使得能够探索髓样细胞对癌基因激活的黑素细胞的反应而对其进行调控编程，并将重点放在细胞成为癌症前体的初始阶段。激素诱导性二元系统可以暂时控制黑色素细胞中不同Ras癌基因（NRas Q61K ，HRas G12V 和KRas G12V ）的表达，导致黑色素细胞的增殖和形态变化。该模型与二元细胞特异性生物标签模型耦合，允许在体内进行生物素化并随后分离巨噬细胞或中性粒细胞核，以对其活性转录组进行调控分析。中性粒细胞的核转录谱分析是在对体内黑素瘤的最早前体做出反应时进行的，揭示了可能促进黑素瘤进展的调控因子的复杂情况，包括Serpinbl14，Fgf1，Fgf6，Cathepsin H，Galectin 1和Galectin 3。本文介绍的模型提供了一个强大的平台，可用于研究骨髓对黑色素瘤最早的前体的反应。

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