Hexameric VCP/p97 reprograms transcription by organizing enhancers with the ASPSCR1-TFE3 fusion oncoprotein

ABSTRACT: Aberrant transcription in alveolar soft part sarcoma (ASPS) is orchestrated by the fusion oncoprotein, ASPSCR1-TFE3, resulting from a gene fusion created by a t(X;17) chromosomal translocation. Proteomic analysis of co-immunoprecipitated ASPSCR1-TFE3 complexes revealed strong enrichment of VCP/p97, an AAA+ ATPase with known segregase function. VCP and ASPSCR1-TFE3 co-distributed across chromatin and were associated with active enhancers, indicated by flanking peaks of H3K27ac that assemble into higher order chromatin structures by HiChIP. Positive and negative genetic experiments with ASPSCR1-TFE3 and VCP demonstrated that they function co-dependently for cancer cell proliferation, colony formation, enhancer activation, chromatin conformation, and transcription. The VCP associating with ASPSCR1-TFE3 was found by native gel and electron microscopy to be assembled into homo-hexamers. Disruption of VCP hexamer assembly or enzymatic function inhibited the transcriptional impact of ASPSCR1-TFE3. Thus, a segregase was found to bind chromatin and assemble into 3-dimensional structures as a co-factor of transcriptional regulation.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Cell Culture

DISEASE(S): Alveolar Soft Part Sarcoma

SUBMITTER: Gian Luca Negri  

LAB HEAD: Gregg Morin

PROVIDER: PXD022515 | Pride | 2023-11-23

REPOSITORIES: Pride