Regulation of Alternative pre-mRNA Splicing during Cell Differentiation, Development and Disease

We study molecular mechanisms that control alternative splicing mRNA precursors. This process is essential for the regulation of eukaryotic genes and plays important roles in human disease, including tumour progression.

Progress during 2017 included 1) synthesis and evaluation of Sudemycin K, a novel drug targeting components of the splicing machinery with anti-tumour properties displaying enhanced activity and versatile chemistry (in collaboration with the group of Mercedes Álvarez and Fernando Albericio, University of Barcelona); 2) identification of a post-transcriptional regulatory network relevant for melanoma cell transformation, coordinated by the RNA binding protein CELF1 (in collaboration with the group of Marisol Soengas, CNIO, Madrid); 3) progress in understanding the molecular basis of the differential sensitivity that 3′ splice sites display to anti-tumour drugs targeting SF3B1, a core component of U2 snRNP involved in 3′ splice site recognition (in collaboration with the group of Manuel Irimia, CRG).

• Role of RNA binding proteins RBM5, RBM6 and RBM10 in the control of cancer cell proliferation through alternative splicing of the Notch regulator NUMB (collaboration with Manuel Serrano, CNIO, Madrid).
• Mechanisms of alternative splicing regulation of the Fas receptor, including a genome-wide screen for regulators.
• Functional network analysis of alternative splicing regulation: role of core components of the splicing machinery on splice site selection and splicing complexes involved in the control of cell division.
• Role of nucleosome positioning and chromatin modifications in alternative splicing regulation (collaboration with the groups of Miguel Beato and Roderic Guigó, CRG).
• Role of lncRNAs in alternative splicing regulation (collaboration with the group of Roderic Guigó, CRG).
• Structure / function analysis of RBM protein OCRE domains (in collaboration with the groups of Michael Sattler, Helmzholtz Zentrum, Munich and Cédric Notredame, CRG).
• Mechanisms of splicing inhibition by anti-tumour drugs targeting components of the core splicing machinery (collaboration with the group of Fernando Albericio, IRB, Barcelona).
• Role of RNA-DNA R-loops in alternative splicing regulation (collaboration with the group of Alberto Kornblihtt, Buenos Aires).
• Role of U2AF35-like factors in male fertility (collaboration with Alfonso Gutiérrez Adán, INIA, Madrid).
• Role of alternative splicing regulation in cell reprogramming (collaboration with Thomas Graf, CRG).
• Functional impact of cancer-associated mutations on SF3B1 function (collaboration with Dolors Colomer and Elias Campo, Hospital Clinic, Barcelona).
• Systematic analysis of regulatory sequences in alternative exons (collaboration with Ben Lehner, CRG).
• Splicing regulatory networks in cellular stress (collaboration with Francesc Posas, UPF).