Shared enhancer gene regulatory networks between wound and oncogenic programs

Abstract

Wound response programs are often activated during neoplastic growth in tumors. In both wound repair and tumor growth, cells respond to acute stress and balance the activation of multiple programs including apoptosis, proliferation, and cell migration. Central to those responses are the activation of 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 regulatory and phenotypic responses is still unclear. Here, we aim to characterize the regulatory states that emerge and cooperate in the wound response, using the Drosophila melanogaster wing disc as a model system, and compare these with cancer cell states induced by rasV12scrib-/- in the eye disc. We used single-cell multiome profiling to derive enhancer Gene Regulatory Networks (eGRNs) by integrating chromatin accessibility and gene expression signals. We identify a 'proliferative' eGRN, active in the majority of wounded cells and controlled by AP-1 and STAT. In a smaller, but distinct population of wound cells, a 'senescent' eGRN is activated and driven by C/EBP-like transcription factors (Irbp18, Xrp1, Slow border, and Vrille) and Scalloped. These two eGRN signatures are found to be active in tumor cells, at both gene expression and chromatin accessibility levels. Our single-cell multiome and eGRNs resource offers an in-depth characterisation of the senescence markers, together with a new perspective on the shared gene regulatory programs acting during wound response and oncogenesis.

Local ecdysone synthesis in a wounded epithelium sustains developmental delay and promotes regeneration inDrosophila

“…This data confirmed phtm induction in wound cells and further refined this expression to 'beta' wound cells (Fig. S4A-B, H) (as defined in Floc'hlay et al, 2023). Expression of sro (shroud), a Halloween gene that acts upstream of phtm in the Ec synthesis pathway, is detected by scSeq throughout the disc independent of injury (Fig.…”

“…Based on a prior RNA-seq study that identified phtm mRNA among a group of injury-induced transcripts in sorted cells from rn>rpr ts blastemas (Khan et al, 2017), we reanalyzed a public single-cell RNA sequencing (scSeq) data derived from injured (rn>egr ts system) and uninjured larval wing discs (Floc'hlay et al, 2023). This data confirmed phtm induction in wound cells and further refined this expression to 'beta' wound cells (Fig.…”

Mutual repression between JNK/AP-1 and JAK/STAT stratifies senescent and proliferative cell behaviors during tissue regeneration

“…Expression of egr induces upd1-3 , the pro-mitogenic cytokines for the JAK/STAT pathway ( S2 Fig ; [ 72 ] ) [ 18 , 26 , 48 , 50 ]. Yet, high JNK-signaling cells in egr- expressing discs that up-regulated a transcriptional upd3 reporter did not exhibit JAK/STAT activity, as assessed by the 10xStat92E-dGFP reporter ( Fig 3A–3G ) [ 73 , 74 ].…”

“…At the level of cell behaviors, JNK/AP-1 and JAK/STAT generate mutually exclusive responses. JNK/AP-1 signaling supports wound behaviors like tissue sealing [ 22 , 23 , 81 ], cell fusion [ 12 ], establishment of paracrine signaling [ 72 ], and, importantly, an apoptosis-resistant state that depends on a G2 cell cycle arrest [ 29 ]. In contrast, JAK/STAT signaling supports compensatory proliferation, potentially via up-regulation of G1-S cyclins such as CycD or CycE [ 142 , 143 ].…”

“…Induction of upd1-3 transcripts in the rn -positive cell population of egr- expressing discs (bottom row) can be clearly detected. Plots were generated using the Scope Wing Atlas [ 72 ]. Source data for quantifications provided in S1 File .…”