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

doi:10.1016/j.celrep.2020.107715

Critical Roles of Translation Initiation and RNA Uridylation in Endogenous Retroviral Expression and Neural Differentiation in Pluripotent Stem Cells

Cell Rep. 2020 Jun 2;31(9):107715. doi: 10.1016/j.celrep.2020.107715.

Authors

Kazutoshi Takahashi¹, Daeun Jeong², Songnan Wang², Megumi Narita³, Xuemei Jin³, Mio Iwasaki³, Samuel D Perli², Bruce R Conklin⁴, Shinya Yamanaka⁵

Affiliations

¹ Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Electronic address: kazutoshi.takahashi@gladstone.ucsf.edu.
² Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
³ Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
⁴ 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.
⁵ 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. Electronic address: syamanaka@gladstone.ucsf.edu.

Abstract

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.

Keywords: endogenous retrovirus; neural differentiation; pluripotency; translation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arylamine N-Acetyltransferase / deficiency
Arylamine N-Acetyltransferase / genetics
Arylamine N-Acetyltransferase / metabolism
Cell Differentiation*
Cell Line
Cell Lineage
Cell Self Renewal
Endogenous Retroviruses / genetics
Endogenous Retroviruses / metabolism*
Gene Editing
Humans
Isoenzymes / deficiency
Isoenzymes / genetics
Isoenzymes / metabolism
Mice
Neurons / cytology*
Neurons / metabolism
Peptide Chain Initiation, Translational
Pluripotent Stem Cells / cytology*
Pluripotent Stem Cells / metabolism
RNA Interference
RNA Nucleotidyltransferases / genetics
RNA Nucleotidyltransferases / metabolism
RNA, Small Interfering / metabolism
RNA, Viral / antagonists & inhibitors
RNA, Viral / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Isoenzymes
RNA, Small Interfering
RNA, Viral
Transcription Factors
Arylamine N-Acetyltransferase
N-acetyltransferase 1
RNA Nucleotidyltransferases
TUT7 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding