Alternative splicing dynamics during somatic cell reprogramming
- Autores: Claudia Vivori
- Directores de la Tesis: Juan Valcárcel Juárez (dir. tes.)
- Lectura: En la Universitat Pompeu Fabra ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Manuel Irimia (presid.), Purificacion Muñoz Canoves (secret.), Nuno Luis Barbosa Morais (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
- Materias:
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- Resumen
Alternative splicing (AS) is a mechanism of post-transcriptional regulation that plays an important role during development and in the maintenance of stem cell pluripotency. The dynamics of AS regulation during somatic cell reprogramming, however, remain poorly understood.
Transient expression of the transcription factor C/EBPα prior to OSKM induction poises mouse B cells for rapid and efficient reprogramming. In this study we identified clusters of AS events with characteristic patterns of changes during reprogramming in this system, which partially overlap with those associated with reprogramming of MEFs. Parallel gene expression profiling of splicing factors, and enrichment of their predicted binding sites in the corresponding AS regions, suggested regulatory mechanisms coordinating key AS changes.
We tested the effect of altering a pronounced switch in isoforms of the transcription factor LEF1, whose overexpression enhanced the induction of pluripotency markers in MEFs reprogramming, with greater effect upon overexpression of the iPS-associated LEF1 isoform. We also studied the involvement of selected predicted AS regulators in enhancing or repressing the induction of pluripotency, validating a reprogramming- promoting role for CPSF3, DDX56, RBM25 and hnRNP UL1 and a repressive function for TIA1 and CELF2.
