Reini Luco is a team leader at the Genome Integrity, RNA and Cancer unit (UMR3348) at l’Institut Curie (Orsay Campus). Her team aims at understanding pre-mRNA alternative splicing dynamics and its role in cancer cell dissemination and metastasis using as a model system the epithelial-to-mesenchymal transition.
Alternative splicing is an RNA process impacting more than 70% of the transcripts. Thanks to the inclusion or exclusion of different pieces of pre-mRNA (intronic and exonic sequences), different mature mRNAs and therefore protein sequences can be obtained from the same genomic sequence. This mechanism is essential to increase the protein diversity and cell adaptability with a limiting genome. Actually, cancer cells are known to take advantage of alternative splicing to acquire new phenotypic traits important for their adaptation to the new tumour microenvironment and become more invasive for metastasis. Understanding alternative splicing regulation will thus allow us to better understand cancer progression and identify innovative new therapeutic targets and/or biomarkers for detecting early metastasis.
Interestingly, during her postdoc at the NIH in Tom Misteli’s lab (USA), Reini identified a novel mechanism of alternative splicing regulation that redefined DNA/RNA boundaries. She found that histone modifications impact splicing factors’ recruitment to the pre-mRNA via chromatin-adaptor complexes that act as a bridge between the chromatin and splicing machinery. As a CNRS group leader at the Institut de Genetique Humaine in Montpellier, she proved that these histone marks are regulated by long non-coding RNAs (NSMB, 2015); that a third of all the alternatively spliced exons expressed in a given cell line are differentially enriched by different subsets of chromatin modifications, creating functionally-relevant splicing-associated chromatin signatures (Nature Comm, 2021); and finally that some of these histone marks are necessary and sufficient to drive the changes in alternative splicing necessary for the acquisition of a more invasive and migratory phenotype during the epithelial-to-mesenchymal transition, a phenomenon intimately ligated to tumour cell dissemination and metastasis (Cell Reports, 2022). Her findings have been rewarded with the CNRS Bronze Medal and she is a member of the cercle FSER and the EpiGeneSys European Network.
Using innovative single-cell and CRISPR RNA (dCas13) and epigenetic (dCas9) editing tools, her team aims now to understand the role of histone modifications in regulating a whole splicing signature important for cell invasion with the final aim of reducing tumour metastasis.