Equipe d’Accueil : Chromatin & RNA splicing
Intitulé de l’Unité : Genome Instability, RNA and Cancer – INSTITUT CURIE
Nom du Responsable de l’Unité : S. Vagner
Nom du Responsable de l’Équipe : Reini LUCO
Adresse : Institut Curie (UMR3348) – Centre de Recherche et Universitaire
Rue Henri Becquerel – Batiment 110 – CS 90030 – Orsay
Responsable de l’encadrement : Reini LUCO
E-mail: reini.luco@curie.fr
Résumé du projet (environ une demi-page)
Alternative splicing shapes cellular phenotypes by generating diverse isoforms from nascent RNA. Deregulation of splicing drives cancer progression, particularly during epithelial-to-mesenchymal transition (EMT), a reprogramming process essential for metastasis. PTBP1, a splicing repressor of the hnRNP family, promotes cancer development by regulating splicing events linked to metabolism, proliferation, and resistance to treatment. Recent findings from the team have connected PTBP1-dependent splicing events, relevant for cell invasiveness, to changes in specific histone marks. However the molecular mechanisms linking the splicing regulator to the chromatin remain unknown.
Using an innovative antibody-based APEX2 proximity labeling approach coupled to chromatin fractionation, we have elaborated the first list of chromatin-related PTBP1 interactors, in which many transcriptional regulators linked to cancer have been identified. Publicly available RNA-seq and ChIP-seq revealed that some of these transcription factors (TF) strongly colocalize with PTBP1 binding sites genome-wide, both at promoters and coding regions of PTBP1-dependent genes. Since we also have evidence of a role for 3D chromatin organization in splicing regulation, we propose that these TFs bring promoters and alternatively spliced exons together in space to help recruit PTBP1 to specialized hubs for a coordinated splicing regulation critical for EMT and cancer metastasis.
The aim of this master internship will be to prove the functional link between these TFs and PTBP1 using CRISPR KO tools, proximity ligation and ChIP-seq and RNA-IP in the EMT context. This would the first time that a transcriptional regulator is shown to coordinate a splicing signature important for EMT dynamics.
Ce projet s’inscrit dans la perspective d’une thèse
Type de financement prévu : Concours école doctorale
Ecole Doctorale de rattachement : Cancérologie : Biologie, Medecine, Santé
Dernières Publications en lien avec le projet :
Segelle, Y. Núñez-Álvarez, A. J. Oldfield, K. M. Webb, P. Voigt, and R. F. Luco, “Histone marks regulate the epithelial-to-mesenchymal transition via alternative splicing,” Cell Rep., vol. 38, no. 7, 2022, doi: 10.1016/j.celrep.2022.110357.
Nabeel-Shah et al., “C2H2-zinc-finger transcription factors bind RNA and function in diverse post-transcriptional regulatory processes,” Mol. Cell, vol. 84, no. 19, pp. 3810-3825.e10, Oct. 2024, doi: 10.1016/j.molcel.2024.08.037.
Xiao et al., “Pervasive Chromatin-RNA Binding Protein Interactions Enable RNA-Based Regulation of Transcription,” Cell, vol. 178, no. 1, pp. 107-121.e18, Jun. 2019, doi: 10.1016/j.cell.2019.06.001.