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

Title
2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms
Author
김계성
Keywords
EMBRYONIC STEM-CELLS; DE-NOVO METHYLATION; SELF-RENEWAL; DNA DEMETHYLATION; TET PROTEINS; HISTONE H3; METHYLTRANSFERASE G9A; MOUSE EMBRYOS; PLURIPOTENCY; 5-HYDROXYMETHYLCYTOSINE
Issue Date
2017-04
Publisher
CELL PRESS
Citation
STEM CELL REPORTS, v. 8, no. 5, page. 1312-1328
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.
URI
https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(17)30134-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2213671117301340%3Fshowall%3Dtruehttps://repository.hanyang.ac.kr/handle/20.500.11754/113594
ISSN
2213-6711
DOI
10.1016/j.stemcr.2017.04.001
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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