Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia; Biomedicine Discovery Institute, Development and Stem Cells Program, Monash University, Melbourne, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
Stuart K Archer
Bioinformatics Platform, Monash University, Clayton, Australia
Craig I Dent
School of Biological Sciences, Monash University, Melbourne, Australia
The Francis Crick Institute, London, United Kingdom
Traude H Beilharz
Biomedicine Discovery Institute, Development and Stem Cells Program, Monash University, Melbourne, Australia; Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
Anja S Knaupp
Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia; Biomedicine Discovery Institute, Development and Stem Cells Program, Monash University, Melbourne, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
Christian M Nefzger
Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia; Biomedicine Discovery Institute, Development and Stem Cells Program, Monash University, Melbourne, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
Jose M Polo
Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia; Biomedicine Discovery Institute, Development and Stem Cells Program, Monash University, Melbourne, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia; Biomedicine Discovery Institute, Development and Stem Cells Program, Monash University, Melbourne, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
The establishment and maintenance of pluripotency depend on precise coordination of gene expression. We establish serine-arginine-rich splicing factor 3 (SRSF3) as an essential regulator of RNAs encoding key components of the mouse pluripotency circuitry, SRSF3 ablation resulting in the loss of pluripotency and its overexpression enhancing reprogramming. Strikingly, SRSF3 binds to the core pluripotency transcription factor Nanog mRNA to facilitate its nucleo-cytoplasmic export independent of splicing. In the absence of SRSF3 binding, Nanog mRNA is sequestered in the nucleus and protein levels are severely downregulated. Moreover, SRSF3 controls the alternative splicing of the export factor Nxf1 and RNA regulators with established roles in pluripotency, and the steady-state levels of mRNAs encoding chromatin modifiers. Our investigation links molecular events to cellular functions by demonstrating how SRSF3 regulates the pluripotency genes and uncovers SRSF3-RNA interactions as a critical means to coordinate gene expression during reprogramming, stem cell self-renewal and early development.
