Functional characterization of 5p15.33 ...
Type de document :
Article dans une revue scientifique: Article original
PMID :
URL permanente :
Titre :
Functional characterization of 5p15.33 risk locus in uveal melanoma reveals rs452384 as a functional variant and NKX2.4 as an allele-specific interactor.
Auteur(s) :
Derrien, Anne-Céline [Auteur]
Houy, Alexandre [Auteur]
Ganier, Olivier [Auteur]
Dingli, Florent [Auteur]
Ningarhari, Massih [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
413221|||Sorbonne Université [SU] (VALID)
Mobuchon, Lenha [Auteur]
Espejo Díaz, Maria Isabel [Auteur]
Loew, Damarys [Auteur]
Cassoux, Nathalie [Auteur]
Université Paris Descartes - Paris 5 [UPD5]
Cussenot, Olivier [Auteur]
Cancel-Tassin, Geraldine [Auteur]
Sorbonne Université [SU]
Margueron, Raphael [Auteur]
Sorbonne Université [SU]
Noirel, Josselin [Auteur]
HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université [HESAM]
Zucman-Rossi, Jessica [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
413221|||Sorbonne Université [SU] (VALID)
Rodrigues, Manuel [Auteur]
Stern, Marc-Henri [Auteur]
Houy, Alexandre [Auteur]
Ganier, Olivier [Auteur]
Dingli, Florent [Auteur]
Ningarhari, Massih [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
413221|||Sorbonne Université [SU] (VALID)
Mobuchon, Lenha [Auteur]
Espejo Díaz, Maria Isabel [Auteur]
Loew, Damarys [Auteur]
Cassoux, Nathalie [Auteur]
Université Paris Descartes - Paris 5 [UPD5]
Cussenot, Olivier [Auteur]
Cancel-Tassin, Geraldine [Auteur]
Sorbonne Université [SU]
Margueron, Raphael [Auteur]
Sorbonne Université [SU]
Noirel, Josselin [Auteur]
HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université [HESAM]
Zucman-Rossi, Jessica [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
413221|||Sorbonne Université [SU] (VALID)
Rodrigues, Manuel [Auteur]
Stern, Marc-Henri [Auteur]
Titre de la revue :
American Journal of Human Genetics
Nom court de la revue :
Am J Hum Genet
Numéro :
109
Pagination :
2196-2209
Date de publication :
2022-12-01
ISSN :
1537-6605
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
The TERT/CLPTM1L risk locus on chromosome 5p15.33 is a pleiotropic cancer risk locus in which multiple independent risk alleles have been identified, across well over ten cancer types. We previously conducted a genome-wide ...
Lire la suite >The TERT/CLPTM1L risk locus on chromosome 5p15.33 is a pleiotropic cancer risk locus in which multiple independent risk alleles have been identified, across well over ten cancer types. We previously conducted a genome-wide association study in uveal melanoma (UM), which uncovered a role for the TERT/CLPTM1L risk locus in this intraocular tumor and identified multiple highly correlated risk alleles. Aiming to unravel the biological mechanisms in UM of this locus, which contains a domain enriched in active chromatin marks and enhancer elements, we demonstrated the allele-specific enhancer activity of this risk region using reporter assays. In UM, we identified the functional variant rs452384, of which the C risk allele is associated with higher gene expression, increased CLPTM1L expression in UM tumors, and a longer telomere length in peripheral blood mononuclear cells. Electrophoretic mobility shift assays and quantitative mass spectrometry identified NKX2.4 as an rs452384-T-specific binding protein, whereas GATA4 preferentially interacted with rs452384-C. Knockdown of NKX2.4 but not GATA4 resulted in increased TERT and CLPTM1L expression. In summary, the UM risk conferred by the 5p locus is at least partly due to rs452384, for which NKX2.4 presents strong differential binding activity and regulates CLPTM1L and TERT expression. Altogether, our work unraveled some of the complex regulatory mechanisms at the 5p15.33 susceptibility region in UM, and this might also shed light on shared mechanisms with other tumor types affected by this susceptibility region.Lire moins >
Lire la suite >The TERT/CLPTM1L risk locus on chromosome 5p15.33 is a pleiotropic cancer risk locus in which multiple independent risk alleles have been identified, across well over ten cancer types. We previously conducted a genome-wide association study in uveal melanoma (UM), which uncovered a role for the TERT/CLPTM1L risk locus in this intraocular tumor and identified multiple highly correlated risk alleles. Aiming to unravel the biological mechanisms in UM of this locus, which contains a domain enriched in active chromatin marks and enhancer elements, we demonstrated the allele-specific enhancer activity of this risk region using reporter assays. In UM, we identified the functional variant rs452384, of which the C risk allele is associated with higher gene expression, increased CLPTM1L expression in UM tumors, and a longer telomere length in peripheral blood mononuclear cells. Electrophoretic mobility shift assays and quantitative mass spectrometry identified NKX2.4 as an rs452384-T-specific binding protein, whereas GATA4 preferentially interacted with rs452384-C. Knockdown of NKX2.4 but not GATA4 resulted in increased TERT and CLPTM1L expression. In summary, the UM risk conferred by the 5p locus is at least partly due to rs452384, for which NKX2.4 presents strong differential binding activity and regulates CLPTM1L and TERT expression. Altogether, our work unraveled some of the complex regulatory mechanisms at the 5p15.33 susceptibility region in UM, and this might also shed light on shared mechanisms with other tumor types affected by this susceptibility region.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
Université de Lille
Inserm
CHU Lille
Inserm
CHU Lille
Collections :
Date de dépôt :
2024-01-31T22:10:10Z
2024-09-06T08:02:45Z
2024-09-06T08:02:45Z
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