2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms

Ye Ji Sim, Min Seong Kim, Abeer Nayfeh, Ye Jin Yun, Su Jin Kim, Kyung Tae Park, Chang Hoon Kim, Kye-Seong Kim

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Mouse embryonic stem cells (ESCs) are maintained in serum with leukemia inhibitory factor (LIF) to maintain self-renewal and pluripotency. Recently, a 2i culture method was reported using a combination of MEK inhibition (MEKi) and GSK3 inhibition (GSK3i) with LIF to maintain ESCs in a naive ground state. How 2i maintains a ground state of ESCs remains elusive. Here we show that MEKi and GSK3i maintain the ESC ground state by downregulating global DNA methylation through two distinct mechanisms. MEK1 phosphorylates JMJD2C for ubiquitin-mediated protein degradation. Therefore, MEKi increased JMJD2C protein levels but decreased DNMT3 expression. JMJD2C promotes TET1 activity to increase 5-hydroxymethylcytosine (5hmC) levels. GSK3i suppressed DNMT3 expression, thereby decreasing DNA methylation without affecting 5hmC levels. Furthermore, 2i increased PRDM14 expression to inhibit DNMT3A/B protein expression by promoting G9a-mediated DNMT3A/B protein degradation. Collectively, 2i allows ESCs to maintain a naive ground state through JMJD2C-dependent TET1 activation and PRDM14/G9a-mediated DNMT3A/B protein degradation.

Original languageEnglish
Pages (from-to)1312-1328
Number of pages17
JournalStem Cell Reports
Volume8
Issue number5
DOIs
StatePublished - 2017 May 9

Keywords

  • 2i
  • G9a
  • GSK3i
  • JMJD2C
  • MEKi
  • PRDM14
  • TET1
  • methylation
  • phosphorylation

Fingerprint Dive into the research topics of '2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms'. Together they form a unique fingerprint.

  • Cite this

    Sim, Y. J., Kim, M. S., Nayfeh, A., Yun, Y. J., Kim, S. J., Park, K. T., Kim, C. H., & Kim, K-S. (2017). 2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms. Stem Cell Reports, 8(5), 1312-1328. https://doi.org/10.1016/j.stemcr.2017.04.001