Gene Regulation, Stems Cells and Cancer

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

Group Structure

GROUP LEADER:
Juan Valcárcel (ICREA Research Professor)
STAFF SCIENTIST:
Sophie Bonnal
POSTDOCTORAL FELLOWS:
Elias Bechara, Panagiotis Papasaikas, Lorena Zubovic, Elisabeth Daguenet
STUDENTS:
Camilla Ianonne, Elena Martín, Juan Ramón Tejedor, Luisa Vigevani, Jordi Hernandez (from July 2013)
TECHNICIANS:
Belén Miñana, Vasiliki Michaki, Anna Ribó
VISITOR:
Kiashanee Moodley (from November 2013)

Summary

We study molecular mechanisms that control the removal of introns from mRNA precursors (pre-mRNA splicing) and the regulation of alternative splicing. These processes are essential for expression of eukaryotic genes, expand the coding capacity of the genomes of complex organisms and play important roles in the regulation of tumour progression.

Progress during 2013 includes the discovery of an important genetic circuit controlling the proliferation of cancer cells, based upon antagonistic effects of three RNA binding proteins, RBM5/6 and RBM10, on alternative splicing of the gene NUMB, a regulator of the Notch signalling pathway important for cell growth (Figure 1). Our results show that modulation of this alternative splicing event can regulate cancer cell growth and also that mutations in RBM10, which are frequently found in lung adenocarcinomas, can enhance the production of the NUMB isoform that promotes cell proliferation.

Collaborative projects have also revealed the function in alternative splicing of proteins involved in RNA 3’ end formation and the effects on splicing of synonymous mutations located in cancer driver genes.

NUMB alternative splicing controls cancer cell proliferation. Figure 1. NUMB alternative splicing controls cancer cell proliferation.


Research Projects

  • 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 the group of Eduardo Eyras, UPF-IMIM, Barcelona).
  • CPEB1 coordinates alternative 3’UTR formation with translational regulation (collaboration with the groups of Raúl Méndez, IRB, Barcelona and of Roderic Guigó, CRG).
  • Co-option of the piRNA pathway for germline-specific regulation of C. elegans TOR expression and alternative splicing (in collaboration with the groups of Ben Lehner, CRG, and of Julian Ceron, IDIBELL, Barcelona).
  • Characterization of the effect of deep intronic mutations associated with Limb-girdle muscular dystrophy (collaboration with the groups of Puri Fortes, CIMA and Adolfo López-Munain, CIC bioGUNE).
  • Mechanisms of alternative splicing regulation of the Fas receptor, including a genome-wide screen for regulators and a role for the splicing factor SRSF1 in 3’ splice site repression (collaboration with the groups of Adrian Krainer, CSHL, Cold Spring Harbor, and Fred Allain, ETH, Zurich).
  • Functional network analysis of alternative splicing regulation: role of core components of the splicing machinery on splice site selection.
  • Effect of synonymous mutations on splicing of cancer driver mutations (in collaboration with the groups of Ben Lehner and Toni Gabaldón, CRG).
  • 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-tumor drugs targeting components of the core splicing machinery.

Selected Publications

  1. Bava F-A, Eliscovich C, Ferreira PG, Miñana B, Ben-Dov C, Guigó R, Valcárcel J and Méndez R.
    “CPEB1 coordinates alternative 3′ UTR formation with translational regulation.”
    Nature, 495:121-125 (2013).
  2. Bechara E, Sebestyén E, Bernardis I, Eyras E and Valcárcel J.
    “RBM5, RBM6 and RBM10 differentially regulate NUMB alternative splicing to control cancer cell proliferation.”
    Molecular Cell, 52:720-733 (2013).
  3. Blázquez L, Aiastui A, Goicoechea M, Martins de Araujo M, Avril A, Beley C, García L, Valcárcel J, Fortes P and López de Munain A.
    “In vitro correction of a pseudoexon-generating deep intronic mutation in LGMD2A by antisense oligonucleotides and modified small nuclear RNAs.”
    Human Mutation, 34:1387-1395 (2013).
  4. Cléry A, Sinha R, Anczuków O, Corrionero A, Moursy A, Daubner G, Valcárcel J, Krainer AR and Allain FH.
    “Isolated pseudo-RRMs of SR proteins can regulate splicing using a non-canonical mode of RNA recognition.”
    Proceedings of the National Academy of Sciences, U.S.A., 110:E2802-2811 (2013).