Disruption of OCT4 Ubiquitination Increases OCT4 Protein Stability and ASH2L-B-Mediated H3K4 Methylation Promoting Pluripotency Acquisition.
Disruption of OCT4 Ubiquitination Increases OCT4 Protein Stability and ASH2L-B-Mediated H3K4 Methylation Promoting Pluripotency Acquisition.
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OCT4 泛素化的破坏增加了 OCT4 蛋白的稳定性和 ASH2L-B 介导的 H3K4 甲基化促进多能性的获得。
DOI：
10.1016/j.stemcr.2018.09.001
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发表时间：
2018-10-09
影响因子：
5.9
通讯作者：
Liao B
中科院分区：
文献类型：
--
作者：
Li S;Xiao F;Zhang J;Sun X;Wang H;Zeng Y;Hu J;Tang F;Gu J;Zhao Y;Jin Y;Liao B
OCT4是一种核心的多潜能转录因子，其蛋白水平对胚胎干细胞(ESC)的维持、分化和体细胞重编程至关重要。然而，OCT4蛋白水平在重新编程过程中是如何控制的，在很大程度上仍不清楚。在这里，我们确定了OCT4的泛素结合位点，并报告了WWP2催化的OCT4泛素化的破坏或WWP2的消融显著促进了小鼠胚胎成纤维细胞的多能性诱导效率。从机制上讲，WWP2介导的OCT4泛素化的中断在重新编程过程中提高了OCT4蛋白的稳定性和H3K4的甲基化水平。此外，我们还发现OCT4直接激活了ASH2L-b的表达，ASH2L-B是ASH2L的主要亚型，在ESCs中高表达，是体细胞重编程所必需的。总之，本研究强调了重编程因子的泛素化操作及其与表观遗传调控因子的相互作用对于成功重编程的重要性，为提高多能性诱导的效率开辟了一条新的途径。5个赖氨酸残基是WWP2催化的OCT4的主要泛素化位点，破坏OCT4泛素化促进体细胞重编程突变OCT4泛素化位点增强OCT4的稳定性和H3K4me水平ASH2-B作为OCT4的直接靶点参与体细胞重编程。在本文中，廖和他的同事们证明了5个赖氨酸残基是WWP2催化的OCT4的主要泛素化位点，并且WWP2催化的OCT4泛素化的破坏或WWP2的消融显著地促进了多能性诱导的效率。从机制上讲，WWP2介导的OCT4泛素化的中断在重新编程过程中提高了OCT4蛋白的稳定性和H3K4的甲基化水平。
The protein level of OCT4, a core pluripotency transcription factor, is vital for embryonic stem cell (ESC) maintenance, differentiation, and somatic cell reprogramming. However, how OCT4 protein levels are controlled during reprogramming remains largely unknown. Here, we identify ubiquitin conjugation sites of OCT4 and report that disruption of WWP2-catalyzed OCT4 ubiquitination or ablation of Wwp2 significantly promotes the efficiency of pluripotency induction from mouse embryonic fibroblasts. Mechanistically, disruption of WWP2-mediated OCT4 ubiquitination elevates OCT4 protein stability and H3K4 methylation level during the reprogramming process. Furthermore, we reveal that OCT4 directly activates expression of Ash2l-b, and that ASH2L-B is a major isoform of ASH2L highly expressed in ESCs and required for somatic cell reprogramming. Together, this study emphasizes the importance of ubiquitination manipulation of the reprogramming factor and its interplay with the epigenetic regulator for successful reprogramming, opening a new avenue to improve the efficiency of pluripotency induction. Five lysine residues are major ubiquitination sites of OCT4 catalyzed by WWP2 Disruption of OCT4 ubiquitination promotes somatic cell reprogramming Mutation of OCT4 ubiquitination sites enhances OCT4 stability and H3K4me levels ASH2L-B contributes to somatic cell reprogramming as a direct target of OCT4 In this article, Liao and colleagues show that five lysine residues are major ubiquitination sites of OCT4 catalyzed by WWP2, and that disruption of WWP2-catalyzed OCT4 ubiquitination or ablation of Wwp2 significantly promotes the efficiency of pluripotency induction. Mechanistically, disruption of WWP2-mediated OCT4 ubiquitination elevates OCT4 protein stability and H3K4 methylation level during the reprogramming process.
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影响因子：
23.9
作者：
Buckley, Shannon M.;Aranda-Orgilles, Beatriz;Strikoudis, Alexandros;Apostolou, Effie;Loizou, Evangelia;Moran-Crusio, Kelly;Farnsworth, Charles L.;Koller, Antonius A.;Dasgupta, Ramanuj;Silva, Jeffrey C.;Stadtfeld, Matthias;Hochedlinger, Konrad;Chen, Emily I.;Aifantis, Iannis
通讯作者：
Aifantis, Iannis
重编程因子表达引发了广泛的靶向染色质重塑。
影响因子：
23.9
作者：
Koche RP;Smith ZD;Adli M;Gu H;Ku M;Gnirke A;Bernstein BE;Meissner A
通讯作者：
Meissner A
影响因子：
3.7
作者：
Saxe JP;Tomilin A;Schöler HR;Plath K;Huang J
通讯作者：
Huang J
影响因子：
64.8
作者：
Kim, Jeong Beom;Greber, Boris;Schoeler, Hans R.
通讯作者：
Schoeler, Hans R.
通过不同的 WWP2 泛素连接酶异构体选择性靶向激活和抑制性 Smad，差异调节 TGFβ 信号传导和 EMT。
影响因子：
8
作者：
Soond, S. M.;Chantry, A.
通讯作者：
Chantry, A.