Shared enhancer gene regulatory networks between wound and oncogenic programs
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.
Single-cell sequencing data and aligned matrices have been deposited in GEO (accession code GSE205401)
Shared enhancer gene regulatory networks between wound and oncogenic programsNCBI Gene Expression Omnibus, GSE205401.
Single-cell transcriptomic analysis of 96hour AEL wild type wing imaginal discsNCBI Gene Expression Omnibus,GSE133204.
Gene expression atlas of a developing tissue by single cell expression correlation analysisNCBI Gene Expression Omnibus,GSE127832.
Single-cell transcriptomic analysis of the scrib mutant wing imaginal discsNCBI Gene Expression Omnibus,GSE130566.
Article and author information
European Research Council (724226_cisCONTROL)
- Valerie M Christiaens
- Gert J Hulselmans
- Stein Aerts
Fonds Wetenschappelijk Onderzoek (G0C0417N)
- Xiaojiang Quan
- Duygu Koldere
Fonds Wetenschappelijk Onderzoek (G094121N)
- Swann Floc'hlay
Deutsche Forschungsgemeinschaft (EXC-2189)
- Anne Classen
Deutsche Forschungsgemeinschaft (CL490/3-1)
- Anne Classen
Deutsche Forschungsgemeinschaft (EXC 2030)
- Mirka Uhlirova
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Utpal Banerjee, University of California, Los Angeles, United States
- Received: June 17, 2022
- Accepted: May 2, 2023
- Accepted Manuscript published: May 3, 2023 (version 1)
© 2023, Floc'hlay et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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