Faculté des Sciences
Faculté des Sciences

Characterizing the Role of the Cohesin Loader NIPBL in Ewing Sarcoma

Mafrica, Cléa ULiège
Promotor(s) : Dequiedt, Franck ULiège ; Fettweis, Grégory ULiège
Date of defense : 5-Sep-2023 • Permalink :
Title : Characterizing the Role of the Cohesin Loader NIPBL in Ewing Sarcoma
Translated title : [fr] Charactérisation du rôle du cohesin loader NIPBL dans le sarcome Ewing
Author : Mafrica, Cléa ULiège
Date of defense  : 5-Sep-2023
Advisor(s) : Dequiedt, Franck ULiège
Fettweis, Grégory ULiège
Committee's member(s) : Meyer, Patrick ULiège
JOSSE, Claire ULiège
Struman, Ingrid ULiège
Language : English
Number of pages : 62
Keywords : [en] NIPBL, cohesin, Ewing sarcoma, EWS-FLI1
Discipline(s) : Life sciences > Biochemistry, biophysics & molecular biology
Research unit : Laboratory of Gene Expression and Cancer, GIGA-Molecular Biology of Diseases
Target public : Researchers
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


[en] Ewing’s sarcoma tumors are mainly driven by a single genetic mutation, the fusion of a FET protein and an ETS transcription factor, which in 85% of cases is the oncogenic fusion EWS-FLI1 (EF1). Emerging evidence demonstrated that the EWS-FLI1 fusion protein promotes some 3D structure change of the genome of Ewing sarcoma cells at multiple scales, including enhancer-promoter chromatin loops.
The cohesin complex has several roles in the cell cycle: cohesion of the sister chromatids, DNA damage repair and as well contribution to the 3D genome organization, which plays a role in gene regulation by bringing enhancers and promoters into close proximity. Interestingly, in 20% of cases, patients were identified to carry, a mutation in the gene STAG2 coding for the STAG2 protein. STAG2 is a subunit of the cohesin complex, highlighting its relevance in the disease. The subject of this thesis focuses on this last essential role of the cohesin complex.
In a previous study, a member of the laboratory demonstrated that the glucocorticoid receptor, GR, can recruit NIPBL after glucocorticoid induction by direct physical interaction at the glucocorticoid element to promote enhancer-promoter loops.
The aim of this project is to find out whether the cohesin loader, NIPBL, directly interacts with EF1. In addition, if the interaction occurs, the dependence of NIPBL on EF1 to be recruited at EF1 target genes cis-regulatory regions will be investigated. Furthermore, the influence of long-range regulation by NIPBL on EF1 target gene expression after NIPBL knockdown (KD) will be evaluated.
Our results showed that EF1 c-ter domain (FLI1) physically interacts with the cohesin loader NIPBL by GST-pull down. Next, we found that EF1 is determinant for the recruitment of NIPBL at the cis-regulatory regions, such as the ones of the PRKCB gene, an EF1 target. We also highlighted that long-range gene regulation mediated by NIPBL can influence the regulation of EF1 target gene expression.
Furthermore, it appears that long-range gene regulation may cooperate or interfere with other enhancer-promoter communication depending on the localization of EF1 binding to cis-regulatory regions compared to the transcriptional start site (TSS) of EF1 target genes. Moreover, the phenotypes observed in NIPBL KD have affected both the EWS-FLI1low state by impairing cell migration and the EWS-FLI1high state by reducing the proliferation of Ewing sarcoma cells (as observed by Dr. Fettweis).
Our research may lead to a new model of transcriptional regulation dependent on the recruitment of NIPBL by oncogenic transcription factors. These results demonstrate the important role of NIPBL in Ewing sarcoma, leading to a potential new therapeutic target.



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  • Mafrica, Cléa ULiège Université de Liège > Master bioch. & biol. mol. & cel., à fin.


Committee's member(s)

  • Meyer, Patrick ULiège Université de Liège - ULiège > Département des sciences de la vie > Biologie des systèmes et bioinformatique
    ORBi View his publications on ORBi
  • JOSSE, Claire ULiège Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'oncologie médicale
    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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