SUMMARY OF RESEARCH

Summary

The tightly regulated process of precursor messenger RNA (pre-mRNA) alternative splicing is a key mechanism to increase the number and complexity of proteins encoded by the genome. The results of deep sequencing-based expression analyses suggest that more than 90% of multi-exon human genes undergo alternative splicing. Changes in the cis- or trans- regulation of this process can cause multiple pathologies as a result of general or specific aberrant pre-mRNA processing underscoring the fundamental importance of this regulatory process. Evidence gathered in recent years has established that transcription and splicing are physically and functionally coupled and that this coupling may be an essential aspect of the regulation of splicing and alternative splicing.

Despite considerable efforts, numerous questions remain regarding the functional significance and global impact of this coupling on cellular and organism homeostasis as well as its underlying molecular mechanisms. In addition to study the molecular events that govern the interactions between the transcription and splicing machineries, we want to go further and provide new insights regarding the molecular mechanisms at work in pathological situations. Our research aims to elucidate the mechanisms of transcription and pre-mRNA processing regulation, which may provide novel and important insights regarding the molecular events that lead to neurological and lymphoproliferative disorders. We also want to identify and characterize the cellular components of these important pathways that should set the groundwork for the understanding of their functions. It is very likely that as this is achieved we will also learn valuable lessons on novel transcriptional/alternative splicing regulatory mechanisms of cellular genes.

1. Transcription/alternative splicing regulation in nervous system

We study the function of WW- and FF-containing proteins in neurogenesis and investigate the molecular mechanism/s by which these factors are affecting the transcription/alternative splicing of endogenous mRNAs that may contribute to the disease phenotype in neurological disorders.

2. Transcription/alternative splicing regulation in cancer

We study the link between the transcription/alternative splicing activity of core spliceosome machinery and the development of haematological malignancies. We are also starting research lines to study the regulation of pre-mRNA splicing in DNA repair, which is essential to maintain genome integrity, to offer new insights into the mechanism of neoplastic transformation.

3. Transcription/alternative splicing regulation in living cells

We investigate the spatial organization and dynamics of transcription and pre-mRNA processing within the highly compartmentalized eukaryotic nucleus, which are fundamental to fully understand how the regulation of gene expression is exerted in the cell.

FUNDING AGENCIES LAST 5 YEARS

- PRPF40B: un regulador epigenético en la enfermedad de Huntington. PROYECTO, J.A.- Retos de la sociedad andaluza 2020, Ref: P20_01269, (2021 - 2023).

- PAPEL DE PRPF40B EN SISTEMA NERVIOSO Y EN LA ENFERMEDAD DE HUNTINGTON. PROYECTO, PN2020 - PROY I+D GENERACION CONOC. - SEGC, Ref: PID2020-118859GB-I00, (2021 - 2024).

- Efecto de la modificación m6A del RNA del SARS-CoV-2 en su ciclo biológico e infectividad. PROYECTO, JA-Proyectos de investigación SARS-COV-2 Andalucía, Ref: CV20-13423, (2020 - 2022).

- DEFINIENDO MECANISMOS DE ACOPLAMIENTO ENTRE TRANSCRIPCION Y SPLICING VINCULADOS A ENFERMEDADES DEGENERATIVAS. PROYECTO, PN2017 - PROY I+D+I - PRG. RETOS DE LA SOCIEDAD, Ref: BFU2017-89179-R, (2018 - 2020).

PUBLICATIONS LAST 5 YEARS

-alonso Rodríguez-Caparrós; Shuizue Tani-ichi; Áurea Casal; Jennifer López-Ros; Carlos Suñé; Koichi Ikuta; Cristina Hernández-Munain, Interleukin-7 receptor signaling is crucial for enhancer-dependent TCR¿ germline transcription mediated through STAT5 recruitment, Frontiers in Immunology, 2022, Vol. 13: 943510, ARTÍCULO, Id:901383

-Rodríguez-Caparrós, A.; Álvarez-Santiago, J.; López-Castellanos, L.; Ruiz-Rodríguez, C.; Valle-Pastor, M.J.; López-Ros, J.; Angulo, Ú.; Andrés-León, E.; Suñé, C.; Hernández-Munain, C., Differently Regulated Gene-Specific Activity of Enhancers Located at the Boundary of Subtopologically Associated Domains: TCRα Enhancer, Journal of Immunology, 2022, Vol. 208: 910-928, ARTÍCULO, Id:888147

-Payán-Bravo, L.; Fontalva, S.; Peñate, X.; Cases, I.; Guerrero-Martínez, J.A.; Pareja-Sánchez, Y.; Odriozola-Gil, Y.; Lara, E.; Jimeno-González, S.; Suñé, C.; Muñoz-Centeno, M.C.; Reyes, J.C.; Chávez, S., Human prefoldin modulates co-transcriptional pre-mRNA splicing, Nucleic Acids Research, 2021, Vol. 49: 6267-6280, ARTÍCULO, Id:852208

-Alonso Rodríguez-Caparrós; Jesús Álvarez-Santiago; María Jesús del Valle-Pastor; Carlos Suñé; Jennifer López-Ros; Cristina Hernández-Munain, Regulation of T-cell Receptor Gene Expression by Three-Dimensional Locus Conformation and Enhancer Function, International Journal of Molecular Sciences, 2020, Vol. 21: 847822-8478, ARTÍCULO DE REVISIÓN, Id:827731

-Suñé-Pou, M.; Limeres, M.J.; Moreno-Castro, C.; Hernández-Munain, C.; Suñé-Negre, J.M.; Cuestas, M.L.; Suñé, C., Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease, Front. Genet., 2020, Vol. 11: 731, ARTÍCULO DE REVISIÓN, Id:812280

-Prieto-Sánchez, S.; Moreno-Castro, C.; Hernández-Munain, C.; Suñé, C., Drosophila Prp40 localizes to the histone locus body and regulates gene transcription and development, Journal of Cell Science, 2020, Vol. 133: 7-jcs239509, ARTÍCULO, Id:806189

-Moreno-Castro, C.; Prieto-Sánchez, S.; Sánchez-Hernández, N.; Hernández-Munain, C.; Suñé, C., Role for the splicing factor TCERG1 in Cajal body integrity and snRNP assembly, Journal of Cell Science, 2019, Vol. 132: 22-jcs232728, ARTÍCULO, Id:780943

-Limeres, M.J.; Suñé-Pou, M.; Prieto-Sánchez, S.; Moreno-Castro, C.; Nusblat, A.D.; Hernández-Munain, C.; Castro, G.R.; Suñé, C.; Suñé-Negre, J.M.; Cuetsas, M.L., Development and characterization of an improved formulation of cholesteryl oleate-loaded cationic solid-lipid nanoparticles as an efficient non-viral gene delivery system, Colloids and Surfaces B: Biointerfaces, 2019, Vol. 184: 110533, ARTÍCULO, Id:780138

-Suñé-Pou, M.; Limeres, M.J.; Nofrerias, I.; Nardi-Ricart, A.; Prieto-Sánchez, S.; El-Yousfi, Y.; Pérez-Lozano, P.; García-Montoya, E.; Miñarro-Carmona, M.; Ticó, J.R.; Hernández-Munain, C.; Suñé, C.; Suñé-Negre, J.M., Improved synthesis and characterization of cholesteryl oleate-loaded cationic solid lipid nanoparticles with high transfection efficiency for gene therapy applications, Colloids and Surfaces B: Biointerfaces, 2019, Vol. 180: 159-167, ARTÍCULO, Id:763123

-Marine Pons; Silvia Prieto; Laetitia Miguel; Thierry Frebourg; Dominique Campion; Carlos Suñé; Magalie Lecourtois, Identification of TCERG1 as a new genetic modulator of TDP-43 production in Drosophila, Acta neuropathologica communications, 2018, Vol. 6: 138-, ARTÍCULO, Id:733070

-Suñé-Pou, M.; Prieto-Sánchez, S.; El Yousfi, Y.; Boyero-Corral, S.; Nardi-Ricart, A.; Nofrerias-Roig, I.; Pérez-Lozano, P.; García-Montoya, E.; Miñarro-Carmona, M.; Ticó, J.R.; Suñé-Negre, J.M.; Hernández-Munain C; Suñé, C., Cholesteryl oleate-loaded cationic solid lipid nanoparticles as carriers for efficient gene-silencing therapy, International journal of nanomedicine, 2018, Vol. 13: 3223-3233, ARTÍCULO, Id:727236

DOCTORAL THESES LAST 5 YEARS