Shared enhancer gene regulatory networks between wound and oncogenic programs [RNA]. Shared enhancer gene regulatory networks between wound and oncogenic programs [RNA]

Wound response programs are often activated during neoplastic growth in tumors. In both systems, cells respond to acute stress and balance the activation of multiple programs including apoptosis, proliferation, and cell migration. Central to this response are the JNK/MAPK and JAK/STAT signaling pathways. Yet, to what extent these signaling cascades interact at the cis-regulatory level, and how they orchestrate different phenotypic responses is still unclear. Here, we aim to characterize the cellular states that emerge and cooperate in the wound response, using the Drosophila melanogaster wing disc as a model system. We used single-cell multi-omics profiling to derive enhancer Gene Regulatory Networks (eGRNs) from chromatin accessibility, transcription factor binding motif and gene expression signals. We identify the eGRNs being activated following a transient wound induction, and compare them with the scRNA profiles obtained from a persistent induction of the rasv12 scrib-/- oncogenic driver. We detect a small cell population in the wound that activates a senescence program that is shared with cancer cells. This population is characterized by the C/EBP-like transcription factors Irbp18, Xrp1, slow-border and vrille. Our single-cell multiome and eGRNs resource offers a new perspective on gene regulation in the normal and wounded wing disc. Overall design: Wild-type wing imaginal discs with induced Xrp1 expression were dissected and analysed using RNA-seq experiments

肿瘤发生过程中通常会激活伤口应答程序。在两类相关系统中，细胞会响应急性应激，并平衡凋亡、增殖及细胞迁移等多种程序的激活。JNK/MAPK与JAK/STAT信号通路是该应答的核心调控环节。然而，这些信号级联反应在顺式调控（cis-regulatory）层面的互作程度，以及它们如何协调不同表型应答的机制仍不明确。本研究以黑腹果蝇（Drosophila melanogaster）翅成虫盘为模型系统，旨在解析伤口应答中出现并协同发挥作用的细胞状态。我们通过单细胞多组学分析（single-cell multi-omics profiling），从染色质可及性、转录因子结合基序及基因表达信号中构建增强子基因调控网络（enhancer Gene Regulatory Networks, eGRNs）。我们鉴定了瞬时伤口诱导后激活的eGRNs，并将其与持续性诱导rasv12 scrib-/-致癌驱动因子所获得的单细胞RNA表达谱进行对比分析。我们在伤口样本中检测到一小群细胞，它们激活了与癌细胞共有的衰老程序。该细胞群的特征为表达C/EBP样转录因子Irbp18、Xrp1、slow-border及vrille。本研究的单细胞多组学及eGRNs数据集，为正常及伤口处理的翅成虫盘的基因调控研究提供了全新视角。实验设计：对诱导表达Xrp1的野生型翅成虫盘进行解剖，并通过RNA测序（RNA-seq）实验完成分析。