Multiphasic and Dynamic Changes in Alternative Splicing during Induction of Pluripotency Are Coordinated by Numerous RNA-Binding Proteins

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Benjamin Cieply, Juw Won Park, Angela Nakauka-Ddamba, Thomas W. Bebee, Yang Guo, Xuequn Shang, Christopher J. Lengner, Yi Xing, Russ P. Carstens
Alternative splicing (AS) plays a critical role in cell fate transitions, development, and disease. Recent studies have shown that AS also influences pluripotency and somatic cell reprogramming. We profiled transcriptome-wide AS changes that occur during reprogramming of fibroblasts to pluripotency. This analysis revealed distinct phases of AS, including a splicing program that is unique to transgene-independent induced pluripotent stem cells (iPSCs). Changes in the expression of AS factors Zcchc24, Esrp1, Mbnl1/2, and Rbm47 were demonstrated to contribute to phase-specific AS. RNA-binding motif enrichment analysis near alternatively spliced exons provided further insight into the combinatorial regulation of AS during reprogramming by different RNA-binding proteins. Ectopic expression of Esrp1 enhanced reprogramming, in part by modulating the AS of the epithelial specific transcription factor Grhl1. These data represent a comprehensive temporal analysis of the dynamic regulation of AS during the acquisition of pluripotency.

Graphical abstract

Teaser

Cieply et al. show that post-transcriptional gene regulation during induced pluripotency of mouse embryo fibroblasts involves temporally coordinated changes in alternative splicing that is mediated by multiple splicing factors. One such factor, Esrp1, which is activated at the critical MET phase, and its target gene, Grhl1, enhance reprogramming efficiency.


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