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Role of the cohesin loader NIPBL in Ewing Sarcoma

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Gilson, Elise ULiège
Promotor(s) : Dequiedt, Franck ULiège ; Fettweis, Grégory ULiège
Date of defense : 3-Sep-2024 • Permalink : http://hdl.handle.net/2268.2/21068
Details
Title : Role of the cohesin loader NIPBL in Ewing Sarcoma
Translated title : [fr] Rôle du chargeur de cohésine NIPBL dans le sarcome d'Ewing
Author : Gilson, Elise ULiège
Date of defense  : 3-Sep-2024
Advisor(s) : Dequiedt, Franck ULiège
Fettweis, Grégory ULiège
Committee's member(s) : JOSSE, Claire ULiège
Twizere, Jean-Claude ULiège
Struman, Ingrid ULiège
Language : English
Number of pages : 70
Keywords : [en] Ewing Sarcoma, EWS-FLI1, NIPBL, PPI
Discipline(s) : Life sciences > Biochemistry, biophysics & molecular biology
Target public : Researchers
Professionals of domain
Student
Institution(s) : Université de Liège, Liège, Belgique
Degree: Master en biochimie et biologie moléculaire et cellulaire, à finalité approfondie
Faculty: Master thesis of the Faculté des Sciences

Abstract

[en] Ewing sarcoma is an aggressive pediatric cancer primarily driven by the fusion protein EWS-FLI1 (EF1), which functions as an aberrant transcription factor. This oncogenic fusion protein is known to reprogram the gene expression landscape of tumor cells, contributing to uncontrolled proliferation and metastatic behavior. Recent studies have implicated EF1 in the disruption of 3D chromatin structure by altering topologically associating domain (TAD) boundaries and creating transcriptional hubs, which promote the formation of novel super-enhancers. These structural changes in chromatin involve the cohesin complex, and by extension, the cohesin loader NIPBL, which plays a critical role in establishing an oncogenic of the genome. Interestingly, our lab recently accumulated evidence that suggests a functional interaction between NIPBL and EF1, highlighting a potential cooperative role in reprogramming chromatin structure to favor oncogenic transcriptional programs in Ewing sarcoma.
This study focused on exploring the direct physical interaction between NIPBL and EF1 to understand its contribution to the oncogenic transformation in Ewing sarcoma.
Using a gaussian luciferase complementation assay, we confirmed a probable direct physical interaction between EF1 and NIPBL. This interaction involves the N-terminal domain of EF1, mediated by the SGQQS repeats, the C-terminal domain of EF1, mediated by the LxxLL-like motif, and the N-terminal region of NIPBL. Notably, the component of NIPBL’s N-terminal region that interacts with EF1 does not involve the LxxLL motif but may be related to a glutamine-rich region. Additionally, we generated interesting EF1 mutants with reduced interaction with NIPBL while retaining transactivation capabilities. Furthermore, we observed that other FET fusions can interact with NIPBL, and, like EF1, this interaction is independent of the NIPBL LxxLL motif.
These findings not only deepen our understanding of the molecular underpinnings of Ewing sarcoma but also open up new avenues for targeted therapies that disrupt key protein-protein interactions essential for the maintenance of the oncogenic phenotype. Further studies are needed to validate these interactions in vivo and to develop specific inhibitors that could effectively target the NIPBL-EF1 interaction, offering hope for more effective and less toxic treatment strategies for patients with Ewing sarcoma.


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Author

  • Gilson, Elise ULiège Université de Liège > Master bioch. & biol. mol. , fin. approf.

Promotor(s)

Committee's member(s)

  • JOSSE, Claire ULiège Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'oncologie médicale
    ORBi View his publications on ORBi
  • Twizere, Jean-Claude ULiège Université de Liège - ULiège > Département GxABT > Microbial technologies
    ORBi View his publications on ORBi
  • Struman, Ingrid ULiège Université de Liège - ULiège > Département des sciences de la vie > Département des sciences de la vie
    ORBi View his publications on ORBi
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