The syntenic long non-coding RNA DANCR is an essential regulator of zebrafish development and a human melanoma oncogene

Long non-coding RNAs (lncRNAs) play crucial roles in regulating gene expression. Some are essential for organismal development and physiology, and they can contribute to diseases such as cancer. Whilst most lncRNAs exhibit little sequence similarity, conservation of lncRNA transcription relative to neighbouring protein-coding genes suggests potential functional significance. Nevertheless, most positionally equivalent lncRNAs are uncharacterized and it remains unclear whether they exert similar roles in distant species. Here, we identified syntenic melanoma-associated lncRNAs predicted to be components of the MITF gene regulatory network in human melanoma, with positionally equivalent transcripts in zebrafish. Among these, we prioritized Differentiation Antagonizing Non-Protein Coding RNA (DANCR), a cancer-associated lncRNA critical for maintaining somatic progenitor cells in human models, for functional investigation. Dancr is a multi-exonic, cytoplasmically enriched lncRNA transcribed from syntenic regions in the human and zebrafish genomes. MITF and c-MYC, key melanoma transcription factors, regulate human DANCR expression and melanoma patients with high DANCR display significantly decreased survival. DANCR is a melanoma oncogene that controls cancer-associated gene expression networks and promotes human melanoma cell proliferation and migration. Zebrafish dancr is dynamically expressed across multiple different cell types in the developing embryo, regulates genes involved in cell death, and is essential for embryonic development. Our work suggests that cancer-critical lncRNAs such as Dancr, expressed from similar regions in vertebrate genomes, may regulate related genes and processes involved in both embryonic development and tumorigenesis across species. RNA-sequencing of DANCR loss-of-function human melanoma cells and whole zebrafish embryos and controls

长链非编码RNA（long non-coding RNAs, lncRNAs）在基因表达调控中发挥关键作用。部分长链非编码RNA对生物体发育与生理功能至关重要，且可参与癌症等疾病的发生发展。尽管多数长链非编码RNA的序列相似性极低，但长链非编码RNA的转录相对于邻近蛋白编码基因的保守性，提示其可能具有潜在的功能重要性。然而，绝大多数位置等效的长链非编码RNA尚未被功能表征，且目前仍不清楚它们在远缘物种中是否发挥相似功能。本研究鉴定了同线（syntenic）黑色素瘤相关长链非编码RNA，这类RNA被预测为人类黑色素瘤中小眼畸形相关转录因子（MITF）基因调控网络的组成成分，且在斑马鱼中存在位置等效的转录本。其中，我们优先选择了分化拮抗非蛋白编码RNA（Differentiation Antagonizing Non-Protein Coding RNA, DANCR）开展功能研究——该癌症相关长链非编码RNA在人类模型中对维持体细胞祖细胞功能至关重要。Dancr是一种多外显子、胞质富集的长链非编码RNA，由人类与斑马鱼基因组中的同线区域转录而来。关键黑色素瘤转录因子MITF与c-MYC可调控人类DANCR的表达，且高表达DANCR的黑色素瘤患者生存率显著降低。DANCR是一种黑色素瘤致癌基因，可调控癌症相关基因表达网络，并促进人类黑色素瘤细胞的增殖与迁移。斑马鱼dancr在发育胚胎的多种细胞类型中呈动态表达，可调控细胞死亡相关基因的表达，且对胚胎发育不可或缺。本研究提示，脊椎动物基因组相似区域表达的Dancr这类癌症关键长链非编码RNA，可能在跨物种的胚胎发育与肿瘤发生过程中调控相关基因与生物学过程。本研究对DANCR功能缺失型人类黑色素瘤细胞、完整斑马鱼胚胎及对照样本开展了RNA测序（RNA-sequencing）