Critical Roles of Translation Initiation and RNA Uridylation in Endogenous Retroviral Expression and Neural Differentiation in Pluripotent Stem Cells
Kazutoshi Takahashi,
Daeun Jeong,
Songnan Wang,
Megumi Narita,
Xuemei Jin,
Mio Iwasaki,
Samuel D. Perli,
Bruce R. Conklin,
Shinya Yamanaka
Affiliations
Kazutoshi Takahashi
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Corresponding author
Daeun Jeong
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
Songnan Wang
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
Megumi Narita
Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
Xuemei Jin
Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
Mio Iwasaki
Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
Samuel D. Perli
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
Bruce R. Conklin
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Departments of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA
Shinya Yamanaka
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Corresponding author
Summary: Previous studies have suggested that the loss of the translation initiation factor eIF4G1 homolog NAT1 induces excessive self-renewability of naive pluripotent stem cells (PSCs); yet the role of NAT1 in the self-renewal and differentiation of primed PSCs is still unclear. Here, we generate a conditional knockout of NAT1 in primed PSCs and use the cells for the functional analyses of NAT1. Our results show that NAT1 is required for the self-renewal and neural differentiation of primed PSCs. In contrast, NAT1 deficiency in naive pluripotency attenuates the differentiation to all cell types. We also find that NAT1 is involved in efficient protein expression of an RNA uridyltransferase, TUT7. TUT7 is involved in the neural differentiation of primed PSCs via the regulation of human endogenous retrovirus accumulation. These data demonstrate the essential roles of NAT1 and TUT7 in the precise transition of stem cell fate.
