Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells.
Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells.
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DOI：
10.1038/nature23274
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发表时间：
2017-08-10
期刊：
影响因子：
64.8
通讯作者：
Hochedlinger K
中科院分区：
文献类型：
--
作者：
Choi J;Huebner AJ;Clement K;Walsh RM;Savol A;Lin K;Gu H;Di Stefano B;Brumbaugh J;Kim SY;Sharif J;Rose CM;Mohammad A;Odajima J;Charron J;Shioda T;Gnirke A;Gygi S;Koseki H;Sadreyev RI;Xiao A;Meissner A;Hochedlinger K
在LIF（2 i/L）存在下，两种小分子同时激活Wnt通路和抑制Mapk信号传导，诱导小鼠胚胎干细胞（ESC）处于幼稚状态，类似于植入前胚胎的内细胞团（ICM）。由于ICM在体内仅短暂存在，因此尚不清楚幼稚ESC在体外的持续繁殖如何影响其稳定性和功能性。在这里，我们表明，在2 i/L的男性胚胎干细胞的长期培养导致不可逆的表观遗传和基因组的变化，损害他们的发育潜力。此外，我们发现在常规血清/LIF（S/L）培养基中培养的雌性ESC与在2 i/L培养基中培养的雄性ESC表型相似。从机制上讲，我们证明，Mek 1/2抑制主要是负责这些影响，部分通过下调DNA甲基转移酶及其相关的辅因子。最后，我们表明，更换的Mek 1/2抑制剂与Src抑制剂保留表观遗传和基因组的完整性，以及胚胎干细胞的发育潜力。总之，我们的数据表明，虽然ESCs中Mek 1/2的短期抑制有助于维持ICM样表观遗传状态，但长期抑制会导致不可逆的变化，从而损害其发育潜力。
Concomitant activation of the Wnt pathway and suppression of Mapk signaling by two small molecules in the presence of LIF (2i/L) induces a naïve state in mouse embryonic stem cells (ESCs) that resembles the inner cell mass (ICM) of the pre-implantation embryo. Since the ICM exists only transiently in vivo, it remains unclear how sustained propagation of naïve ESCs in vitro affects their stability and functionality. Here we show that prolonged culture of male ESCs in 2i/L results in irreversible epigenetic and genomic changes that impair their developmental potential. Additionally, we find that female ESCs cultured in conventional serum/LIF (S/L) media phenocopy male ESCs cultured in 2i/L. Mechanistically, we demonstrate that Mek1/2 inhibition is predominantly responsible for these effects, in part through downregulation of DNA methyltransferases and their associated cofactors. Finally, we show that replacement of the Mek1/2 inhibitor with a Src inhibitor preserves the epigenetic and genomic integrity as well as developmental potential of ESCs. Taken together, our data suggest that, while short-term suppression of Mek1/2 in ESCs helps maintain an ICM-like epigenetic state, prolonged suppression results in irreversible changes that compromise their developmental potential.
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影响因子：
16.8
作者：
Leitch, Harry G.;McEwen, Kirsten R.;Turp, Aleksandra;Encheva, Vesela;Carroll, Tom;Grabole, Nils;Mansfield, William;Nashun, Buhe;Knezovich, Jaysen G.;Smith, Austin;Surani, M. Azim;Hajkova, Petra
通讯作者：
Hajkova, Petra
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
影响因子：
56.9
作者：
Gaudet, F;Hodgson, JG;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
23.9
作者：
Pastor WA;Chen D;Liu W;Kim R;Sahakyan A;Lukianchikov A;Plath K;Jacobsen SE;Clark AT
通讯作者：
Clark AT