DOT1L inhibition enhances pluripotency beyond acquisition of epithelial identity and without immediate suppression of the somatic transcriptome.
DOT1L inhibition enhances pluripotency beyond acquisition of epithelial identity and without immediate suppression of the somatic transcriptome.
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DOI：
10.1016/j.stemcr.2021.12.004
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发表时间：
2022-02-08
影响因子：
5.9
通讯作者：
Sridharan R
中科院分区：
文献类型：
--
作者：
Wille CK;Sridharan R
抑制组蛋白3赖氨酸79（H3K79）甲基转移酶，端粒沉默1样（DOT1L）的破坏物，增加了将体细胞重编程为诱导多能干细胞（iPSC）的效率。在这里，我们发现，尽管H3 K79甲基化在体细胞中数千个活跃转录的基因上富集，但DOT 1L抑制（DOT 1Li）并不会立即导致体细胞转录谱的关闭，从而实现向多能性的转变。与流行的观点相反，DOT1Li促进iPSC的产生，超越了间充质到上皮的转变，甚至从已经上皮的细胞类型。DOT1Li在重编程的中点最有效，部分原因是抑制了在重编程后期持续存在的Nfix。重要的是，单个基因的调控不能取代DOT1Li，这表明H3K79甲基化在维持细胞身份方面具有多效性。DOT1L是重编程的障碍，特别是在中点DOT1L抑制增加多能性超过MET DOT1L抑制不会立即抑制体细胞表达单一因子不能取代DOT1L抑制的多效性作用在这篇文章中，Wille和Sridharan利用体细胞重编程来揭示神秘的组蛋白修饰H3K79me是多能性获得的障碍，而不仅仅是促进细胞的增殖。上皮状态H3K79甲基转移酶DOT1L的抑制在维持细胞身份方面具有多效性作用，这不能通过调节单个基因来重现。
Inhibiting the histone 3 lysine 79 (H3K79) methyltransferase, disruptor of telomeric silencing 1-like (DOT1L), increases the efficiency of reprogramming somatic cells to induced pluripotent stem cells (iPSCs). Here, we find that, despite the enrichment of H3K79 methylation on thousands of actively transcribed genes in somatic cells, DOT1L inhibition (DOT1Li) does not immediately cause the shutdown of the somatic transcriptional profile to enable transition to pluripotency. Contrary to the prevalent view, DOT1Li promotes iPSC generation beyond the mesenchymal to epithelial transition and even from already epithelial cell types. DOT1Li is most potent at the midpoint of reprogramming in part by repressing Nfix that persists at late stages of reprogramming. Importantly, regulation of single genes cannot substitute for DOT1Li, demonstrating that H3K79 methylation has pleiotropic effects in maintaining cell identity. DOT1L is a barrier of reprogramming, especially at the mid-point DOT1L inhibition increases pluripotency beyond MET DOT1L inhibition does not immediately suppress somatic expression Single factors cannot replace the pleiotropic effects of DOT1L inhibition In this article, Wille and Sridharan utilize somatic cell reprogramming to uncover that the enigmatic histone modification H3K79me is a barrier to pluripotency acquisition beyond the promotion of an epithelial state. Inhibition of the H3K79 methyltransferase, DOT1L, has pleiotropic effects in maintaining cell identity that cannot be recapitulated by modulating individual genes.
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影响因子：
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