The core spliceosomal factor U2AF1 controls cell-fate determination via the modulation of transcriptional networks.
Abdelhamid Mahdi LaarefLaurent ManchonYacine BarecheLaure LapassetJamal TaziPublished in: RNA biology (2020)
Alternative splicing (AS) plays a central role during cell-fate determination. However, how the core spliceosomal factors (CSFs) are involved in this process is poorly understood. Here, we report the down-regulation of the U2AF1 CSF during stem cell differentiation. To investigate its function in stemness and differentiation, we downregulated U2AF1 in human induced pluripotent stem cells (hiPSCs), using an inducible-shRNA system, to the level found in differentiated ectodermal, mesodermal and endodermal cells. RNA sequencing and computational analysis reveal that U2AF1 down-regulation modulates the expression of development-regulating genes and regulates transcriptional networks involved in cell-fate determination. Furthermore, U2AF1 down-regulation induces a switch in the AS of transcription factors (TFs) required to establish specific cell lineages, and favours the splicing of a differentiated cell-specific isoform of DNMT3B. Our results showed that the differential expression of the core spliceosomal factor U2AF1, between stem cells and the precursors of the three germ layers regulates a cell-type-specific alternative splicing programme and a transcriptional network involved in cell-fate determination via the modulation of gene expression and alternative splicing of transcription regulators.
Keyphrases
- cell fate
- atrial fibrillation
- transcription factor
- gene expression
- stem cells
- single cell
- induced pluripotent stem cells
- solid phase extraction
- molecularly imprinted
- dna methylation
- cell therapy
- genome wide
- endothelial cells
- induced apoptosis
- dna binding
- epithelial mesenchymal transition
- genome wide identification
- endoplasmic reticulum stress
- cell death
- long non coding rna
- simultaneous determination
- binding protein