Gene Regulation, Stems Cells and Cancer

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Regulation of Alternative Pre-mRNA Splicing During Cell Differentiation, Development and Disease



GROUP LEADER:
Juan Valcárcel (ICREA Research Professor)
STAFF SCIENTIST:
Sophie Bonnal
POSTDOCTORAL FELLOWS:
Panagiotis Papasaikas, Elisabeth Daguenet, Gwendal Dujardin, Keiko Horiuchi (from April 2014)
STUDENTS:
Camilla Ianonne, Elena Martín, Juan Ramón Tejedor, Luisa Vigevani, Jordi Hernandez, Claudia Vivori (from September 2014)
TECHNICIANS:
Belén Miñana, Anna Ribó
VISITORS:
Maria Fabre, Álvaro Moreno, Gemma Pidelaserra, Doerte Schlessinger, Alexandra Bergfort

Summary


Figure 1. Co-option of the piRNA / Argonaute pathway for the regulation of germline-specific alternative splicing in C. elegans.

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.


Figure 2. Regulation of Fas/CD95 alternative splicing by the Ewing sarcoma protein.

Progress during 2014 includes the discovery of a functional role for small non-coding RNAs (piRNAs) and Argonaute proteins in alternative splicing, including changes during spermatogenesis in C. elegans (Figure 1) linked to the maintenance of transgenerational fertility. Another finding is a role for the Ewing Sarcoma protein (EWS) in the regulation of Fas alternative splicing and the control of programmed cell death (Figure 2).

Collaborative projects revealed the impact of synonymous mutations on RNA processing of cancer driver genes and networks of alternative splicing regulation in cancer.


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.
  • 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).
  • 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.
  • 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-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).

Selected Publications

Supek F, Miñana B, Valcárcel J, Gabaldón T and Lehner B.
“Synonymous mutations frequently act as driver mutations in human cancer.”
Cell, 156:1324-1335 (2014).

Wang I, Hennig J, Jagtap PK, Sonntag M, Valcárcel J and Sattler M.
“Structure, dynamics and RNA binding of the multi-domain splicing factor TIA-1.”
Nucleic Acids Research, 42:5949-5966 (2014).

Paronetto MP, Bernardis I, Volpe E, Bechara E, Sebestyén E, Eyras E and Valcárcel J.
“Regulation of FAS exon definition and apoptosis by the Ewing’s sarcoma protein.”
Cell Reports, 7:1211-1226 (2014).

Barberán-Soler S, Fontondron, L, Lamm AT, Iannone C, Cerón J, Lehner B and Valcárcel J.
“Co-option of the piRNA pathway for germline-specific regulation of C. elegans TOR expression and alternative splicing.”
Cell Reports, 8:1609-1616 (2014).

Vigevani L and Valcárcel J.
“A splicing magic bullet.”
Science, 345:624-625 (2014).