Stem cell reports, 2017-05, Vol.8 (5), p.1312-1328
2017
Details
- Autor(en) / Beteiligte
- Titel
- 2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms
- Ist Teil von
- Stem cell reports, 2017-05, Vol.8 (5), p.1312-1328
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •MEKi increases JMJD2C protein levels and decreases DNMT3 expression in ESCs•JMJD2C promotes TET1 hydroxylase activity to increase global 5hmC levels•GSK3i decreases global DNA methylation without affecting 5hmC levels•2i-induced PRDM14 expression promotes G9a-mediated DNMT3A/B protein degradation In this article, Kim and colleagues show that MEKi and GSK3i maintain the ESC ground state by downregulating global DNA methylation through two distinct mechanisms. MEKi increased JMJD2C protein levels, thereby enhancing TET1 activity, whereas GSK3i decreased DNMT3 family expression. Therefore, they uncover that DNA demethylation pathways under 2i conditions are governed by the JMJD2C/TET1 and PRDM14/G9a/DNMT3 complexes.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2213-6711eISSN: 2213-6711DOI: 10.1016/j.stemcr.2017.04.001Titel-ID: cdi_doaj_primary_oai_doaj_org_article_46b1b14f6c644941b6f93e557c15710d
- Format
- –
- Schlagworte
- Animals, Cell Line, DNA (Cytosine-5-)-Methyltransferases - genetics, DNA (Cytosine-5-)-Methyltransferases - metabolism, DNA Methylation, Epigenesis, Genetic, G9a, Glycogen Synthase Kinase 3 - antagonists & inhibitors, Glycogen Synthase Kinase 3 - metabolism, GSK3i, Induced Pluripotent Stem Cells - cytology, Induced Pluripotent Stem Cells - metabolism, JMJD2C, Jumonji Domain-Containing Histone Demethylases - metabolism, MAP Kinase Kinase 1 - antagonists & inhibitors, MAP Kinase Kinase 1 - metabolism, MEKi, methylation, Mice, Mouse Embryonic Stem Cells - cytology, Mouse Embryonic Stem Cells - metabolism, phosphorylation, PRDM14, Protein Kinase Inhibitors - pharmacology, Proteolysis, TET1, Transcription Factors - genetics, Transcription Factors - metabolism, Ubiquitination