The pluripotent stem cell-specific transcript ESRG is dispensable for human pluripotency

PLoS Genet. 2021 May 25;17(5):e1009587. doi: 10.1371/journal.pgen.1009587. eCollection 2021 May.


Human pluripotent stem cells (PSCs) express human endogenous retrovirus type-H (HERV-H), which exists as more than a thousand copies on the human genome and frequently produces chimeric transcripts as long-non-coding RNAs (lncRNAs) fused with downstream neighbor genes. Previous studies showed that HERV-H expression is required for the maintenance of PSC identity, and aberrant HERV-H expression attenuates neural differentiation potentials, however, little is known about the actual of function of HERV-H. In this study, we focused on ESRG, which is known as a PSC-related HERV-H-driven lncRNA. The global transcriptome data of various tissues and cell lines and quantitative expression analysis of PSCs showed that ESRG expression is much higher than other HERV-Hs and tightly silenced after differentiation. However, the loss of function by the complete excision of the entire ESRG gene body using a CRISPR/Cas9 platform revealed that ESRG is dispensable for the maintenance of the primed and naïve pluripotent states. The loss of ESRG hardly affected the global gene expression of PSCs or the differentiation potential toward trilineage. Differentiated cells derived from ESRG-deficient PSCs retained the potential to be reprogrammed into induced PSCs (iPSCs) by the forced expression of OCT3/4, SOX2, and KLF4. In conclusion, ESRG is dispensable for the maintenance and recapturing of human pluripotency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / genetics
  • Cells, Cultured
  • Cellular Reprogramming
  • Female
  • Gene Silencing
  • Humans
  • Kruppel-Like Factor 4
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • RNA, Long Noncoding / genetics*


  • ESRG lncRNA, human
  • KLF4 protein, human
  • Kruppel-Like Factor 4
  • RNA, Long Noncoding

Grant support

This work was supported by Grants-in-Aid for Scientific Research (20K20585) to K.T. from the Japanese Society for the Promotion of Science (JSPS); a grant from the Core Center for iPS Cell Research (JP21bm0104001) to S.Y., Research Center Network for Realization of Regenerative Medicine from Japan Agency for Medical Research and Development (AMED) to S.Y.; a grant from the Japan Foundation for Applied Enzymology to K.T.; a grant from the Fujiwara Memorial Foundation to K.T.; a grant from the Takeda Science Foundation to K.T.; and the iPS Cell Research Fund to K.T. from Center for iPS Cell Research and Application, Kyoto University. The study was also supported by funding to S.Y. from Mr. H. Mikitani, Mr. M. Benioff, and the L.K. Whittier Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.