{
  "abstract": "Ewing sarcoma (EwS) is an aggressive, human-exclusive tumor typically driven by the EWS::friend leukemia integration 1 (FLI1) fusion protein. To assess whether EWS::FLI1's neomorphic functions depend on evolutionarily recent cofactors, we expressed EWS::FLI1 in Saccharomyces cerevisiae, a minimal system in which the BAF complex is strongly diverged and ETS transcription factors (ETS-TFs), polycomb group (PcG) proteins, and CBP/p300 are absent. We used co-IP/mass spectrometry to map the yeast interactome, ChIP-seq to identify gDNA binding sequences, RNA-seq for gene expression, and engineered reporters to test conversion of GGAA tandem repeats (GGAAμSat) into neoenhancers. We found that the yeast EWS::FLI1 interactome was limited and distinct from its human counterpart, sharing core machinery (RNA polymerase II, FACT) but lacking BAF/SWI-SNF and spliceosome complexes, and showing enrichment for SAGA. EWS::FLI1 binds to hundreds of yeast genomic sites with preference for putative ETS-TF consensus sequences and CA dinucleotide repeats, and redirects RNA polymerase II to EWS::FLI1-bound loci. Yet, EWS::FLI1-expressing cells presented only minimal transcriptional dysregulation, in contrast to the extensive changes observed in human and Drosophila cells. Finally, EWS::FLI1 successfully converted silent GGAAμSat sequences into active enhancers in yeast. This remarkable result occurs despite the absence of homologs for key human activators, such as CBP/p300, suggesting that EWS::FLI1 can mobilize functionally related, nonhomologous pathways to establish neoenhancers at GGAAμSat sites. Altogether, our results indicate that EWS::FLI1's core ability to drive GGAAμSat-dependent gene expression is a conserved, ancient property, while GGAAμSat-independent extensive transcriptome reprogramming depends on animal-specific cofactors and pathways.",
  "abstract_shown": true,
  "affiliations": [
    "Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain.",
    "Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona 08950, Spain.",
    "Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona 08950, Spain.",
    "Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Diego Velázquez",
      "orcid": "0000-0002-5987-2570"
    },
    {
      "affs": [
        0
      ],
      "name": "Cristina Molnar",
      "orcid": "0000-0003-3426-4234"
    },
    {
      "affs": [
        0
      ],
      "name": "Jose Reina",
      "orcid": "0000-0003-3789-4514"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Jaume Mora"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Cayetano Gonzalez",
      "orcid": "0000-0002-5259-3608"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7azcf7k3badaw.bib",
  "cited_by": 0,
  "doi": "10.1093/pnasnexus/pgag329",
  "fulltext_url": "https://europepmc.org/articles/PMC13650706",
  "id": "7azcf7k3badaw",
  "issns": [
    "2752-6542"
  ],
  "landing_url": "https://europepmc.org/article/MED/42857501",
  "language": "eng",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Genomics and Chromatin Dynamics"
    ]
  ],
  "openalex": "W7214666959",
  "pdf_url": "https://europepmc.org/articles/PMC13650706?pdf=render",
  "pmcid": "PMC13650706",
  "pmid": "42857501",
  "published": "2026-09-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7azcf7k3badaw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:16Z",
      "native_id": "MED:42857501",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42857501"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics and Chromatin Dynamics",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Ancient and animal-specific regulatory modes of EWS::FLI1 revealed by a minimal yeast model.",
  "title_text": "Ancient and animal-specific regulatory modes of EWS::FLI1 revealed by a minimal yeast model.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:16Z",
  "url": "https://research.draconitic.com/paper/7azcf7k3badaw",
  "venue": "PNAS nexus",
  "versions": []
}