Shared enhancer gene regulatory networks between wound and oncogenic programs

Author:

Floc’hlay SwannORCID,Balaji Ramya,Christiaens ValerieORCID,González-Blas Carmen BravoORCID,De Winter SeppeORCID,Hulselmans GertORCID,De Waegeneer MaximeORCID,Quan Xiaojiang,Koldere Duygu,Atkins MardelleORCID,Halder GeorgORCID,Classen AnneORCID,Aerts SteinORCID

Abstract

AbstractWound 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. In tumor cells on the other hand, both eGRN signatures are simultaneously active within the same cell. 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.

Publisher

Cold Spring Harbor Laboratory

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