Critical genetic program forDrosophilaimaginal disc regeneration revealed by single-cell analysis

Abstract

Whether regeneration is primarily accomplished by re-activating gene regulatory networks used previously during development or by activating novel regeneration-specific transcriptional programs remains a longstanding question. Currently, most genes implicated in regeneration also function during development. Using single-cell transcriptomics in regenerating Drosophila wing discs, we identified two regeneration-specific cell populations within the blastema. They are each composed of cells that upregulate multiple genes encoding secreted proteins that promote regeneration. In this regenerative secretory zone, the transcription factor Ets21C controls the expression of multiple regenerationpromoting genes. While eliminating Ets21C function has no discernible effect on development, it severely compromises regeneration. This Ets21C-dependent gene regulatory network is also activated in blastema-like cells in tumorous discs, suggesting that pro-regenerative mechanisms can be co-opted by tumors to promote aberrant growth.

Shared enhancer gene regulatory networks between wound and oncogenic programs

“…We further observe an up-regulation of markers of tissue patterning and proliferation in cluster 𝝰 relative to cluster 𝝱, like wingless (wg), Wnt oncogeneanalog 6 (Wnt6) (Figure 1.c, p-adj𝝰/𝝱<10e -3 , log2FC𝝰/𝝱>1) and CyclinE (CycE) (Figure 3.d, log2FC𝝰/𝝱>0.8). In this line, we also find evidence for an up-regulation of the pro-regenerative marker Ets at 21C (Ets21C) (Worley et al, 2021), with a combined enrichment of its gene expression (p-adj<10e -3 , log2FC>8) and its binding motif in cluster 𝝰 (cistarget, NES=3.35). Consistent with the higher enhancer activity of the Stat92E eGRN in wound 𝝰 compared to 𝝱 (Figure 3.a-b), we find a significant overlap between the 𝝰 marker genes and a study that identified JAK/STAT as coordinating cell proliferation during wing disc regeneration (GSEA, NES=1.292) (Katsuyama et al, 2015).…”

Single-Cell Atlas of the Drosophila Leg Disc Identifies a Long Non-Coding RNA in Late Development

“…The integrated dataset overlayed T1, T2, and T3 individual samples and identified four distinct clusters ( Figure 1 D). The largest cluster represented the leg disc epithelium, which expressed epithelial markers Fasciclin 3 ( Fas3 ) and narrow ( nw ) ( Figure 1 E) [ 21 ]. Expression of Sp1 and Ultrabithorax ( Ubx ) confirmed that the cells originated from L3 discs [ 22 , 23 ].…”