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2i 通过两种不同的表观遗传机制维持胚胎干细胞的原始状态。

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

机构信息

Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea.

Department of Pathology and Laboratory Medicine, Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38103, USA.

出版信息

Stem Cell Reports. 2017 May 9;8(5):1312-1328. doi: 10.1016/j.stemcr.2017.04.001. Epub 2017 Apr 27.

DOI:10.1016/j.stemcr.2017.04.001
PMID:28457889
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5425728/
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.

摘要

小鼠胚胎干细胞 (ESCs) 在含有白血病抑制因子 (LIF) 的血清中培养，以维持自我更新和多能性。最近，报道了一种 2i 培养方法，该方法使用 MEK 抑制 (MEKi) 和 GSK3 抑制 (GSK3i) 与 LIF 联合使用，将 ESCs 维持在原始的基础状态。2i 如何维持 ESCs 的基础状态仍然难以捉摸。在这里，我们表明 MEKi 和 GSK3i 通过两种不同的机制下调全局 DNA 甲基化来维持 ESC 的基础状态。MEK1 使 JMJD2C 磷酸化以进行泛素介导的蛋白降解。因此，MEKi 增加了 JMJD2C 蛋白水平，但降低了 DNMT3 的表达。JMJD2C 促进 TET1 活性以增加 5-羟甲基胞嘧啶 (5hmC) 水平。GSK3i 抑制 DNMT3 的表达，从而降低 DNA 甲基化而不影响 5hmC 水平。此外，2i 通过促进 G9a 介导的 DNMT3A/B 蛋白降解来增加 PRDM14 的表达，从而抑制 DNMT3A/B 蛋白的表达。总之，2i 通过 JMJD2C 依赖性 TET1 激活和 PRDM14/G9a 介导的 DNMT3A/B 蛋白降解使 ESCs 能够维持原始基础状态。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/767dc08696d9/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/fcb364d06dfa/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/7ba26498c712/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/6d9d6ce3cfa7/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/ab3c8abb0bd9/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/5f2f63dfdd40/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/4ce2fcb4feba/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/556d4e9dd451/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/767dc08696d9/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/fcb364d06dfa/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/7ba26498c712/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/6d9d6ce3cfa7/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/ab3c8abb0bd9/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/5f2f63dfdd40/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/4ce2fcb4feba/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/556d4e9dd451/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/5425728/767dc08696d9/gr7.jpg

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2
Leukemia inhibitory factor (LIF) withdrawal activates mTOR signaling pathway in mouse embryonic stem cells through the MEK/ERK/TSC2 pathway.白血病抑制因子（LIF）的去除通过 MEK/ERK/TSC2 途径激活小鼠胚胎干细胞中的 mTOR 信号通路。
Cell Death Dis. 2016 Jan 14;7(1):e2050. doi: 10.1038/cddis.2015.387.
3
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FASEB Bioadv. 2025 May 2;7(6):e70012. doi: 10.1096/fba.2024-00216. eCollection 2025 Jun.
4
Vitamin C and MEK Inhibitor PD0325901 Synergistically Promote Oligodendrocytes Generation by Promoting DNA Demethylation.维生素C与MEK抑制剂PD0325901通过促进DNA去甲基化协同促进少突胶质细胞生成。
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5
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