Preprint uses Drosophila to dissect how ETV4 activates GGAA microsatellite neoenhancers linked to Ewing sarcoma

A preprint posted to bioRxiv (not yet peer-reviewed) reports the use of Drosophila as an in vivo system to evaluate the transcriptional requirements of human ETS-family transcription factors at GGAA microsatellite sequences, a class of repeat element implicated in the oncogenesis of Ewing sarcoma.

Ewing sarcoma is characterised by FET::ETS oncogenic fusion proteins — most commonly EWSR1::FLI1 — that convert transcriptionally silent GGAA microsatellites (GGAASats) into functional enhancers, driving aberrant gene expression. Emerging evidence, the authors note, also implicates non-fused ETS factors in activating these repeats in other cancer contexts.

The researchers expressed various human ETS factors in Drosophila and found that ETV4, a full-length ETS transcription factor, uniquely binds and robustly activates GGAASats in a tissue-specific manner. They further show that this activation depends on Cabeza, the Drosophila orthologue of the human FET-family proteins (FUS, EWS, TAF15). The ETS repressor ETV6 was found to strongly inhibit ETV4-mediated GGAASat activation.

The study illustrates how the Drosophila system can be used to characterise the transcriptional machinery underlying a cancer-relevant enhancer mechanism, and identifies Cabeza/FET proteins as cofactors for ETV4 activity at these repeats. As a preprint, the findings have not yet been peer-reviewed and should be treated as preliminary.