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 tumor progression.

Progress during 2018 included the discovery of a function for the U12 spliceosome component ZSRS1 in mouse spermatogenesis (in collaboration with the group of Alfonso Gutiérrez-Adán, INIA, Madrid). Mutant mice expressing a truncated ZRSR1 exhibit severe defects in spermatogenesis, leading to azoospermia and male sterility. This phenotype is associated with increased intron retention of both U2- and U12-type introns in genes with key functions in spermatogenesis and spermatid development. Our results also revealed evidence for functional cross-talk between the major and minor spliceosomes. In addition, a patent application was filed in 2018 to protect the potential therapeutic applications of splicing-modifying antisense oligonucleotides targeting NUMB splicing in lung adenocarcinomas and other cancers.

1. Role of RNA binding proteins RBM5, RBM6 and RBM10 in the control of cancer cell proliferation through alternative splicing (collaborations with the groups of Manuel Serrano, IRB, Barcelona and Francisco X. Real, CNIO, Madrid).

2. Mechanisms of alternative splicing regulation of the Fas receptor, including a systematic analysis of regulatory sequences in alternative exons (collaboration with the group of Ben Lehner, CRG).

3. Functional network analysis of alternative splicing regulation: role of core components of the splicing machinery on splice site selection and splicing complexes involved in tissue-specific splicing and in the control of cell division (collaborations with the groups of Roderic Guigó and Luis Serrano, CRG).

4. Role of RNA-DNA R-loops in alternative splicing regulation (collaboration with the groups of Alberto Kornblihtt (Universidad de Buenos Aires) and Nick Proudfoot (Oxford University).

5. Role of alternative splicing regulation in cell reprogramming (collaboration with the group of Thomas Graf, CRG).

6. Mechanisms of transcription / RNA processing coupling (collaboration with the group of Miguel Beato, CRG).

7. Function and mechanisms of regulation of microexons (in collaboration with the group of Manuel Irimia, CRG).

8. Functional impact of cancer-associated mutations on SF3B1 function (collaboration with the groups of Dolors Colomer and Elias Campo, Hospital Clinic, Barcelona).

9. Splicing regulatory networks in cellular stress (collaboration with the group of Francesc Posas, IRB, Barcelona).

10. Structure / function analysis of the evolution of core splicing factors (collaboration with the group of Cédric Notredame, CRG).

11. Splicing-based mechanisms of drug resistance in melanoma (collaboration with the group of Ana Arance, Hospital Clinic, Barcelona).

Horiuchi K#, Perez-Cerezales# S, Papasaikas P, López-Cardona AP, Ramos-Ibeas P, Laguna-Barraza R, Fonseca Balvis N, Perocuesta E, Fernández-González R, Planells B, Ross PJ, Alén F, Orio L, Rodriguez de Fonseca F, Pintado B, Valcárcel J* and Gutiérrez-Adán A*.
“Impaired spermatogenesis, muscle and erythrocyte function in U12 intron-splicing defective Zrsr1 mutant mice.”
Cell Reports, 23:143-155, 2018. #Co-first authors. *Co-corresponding authors

EPO Patent application “Antisense oligonucleotides and uses thereof” (EP 18162571.6-1111) in order to protect the use of antisense oligonucleotides targeting NUMB exon 9 as potential therapy for lung adenocarcinomas and other tumours.