细胞周期蛋白依赖性激酶1调控胚胎干细胞的整体表观遗传格局。
Cdk1 Controls Global Epigenetic Landscape in Embryonic Stem Cells.
作者信息
Michowski Wojciech, Chick Joel M, Chu Chen, Kolodziejczyk Aleksandra, Wang Yichen, Suski Jan M, Abraham Brian, Anders Lars, Day Daniel, Dunkl Lukas M, Li Cheong Man Mitchell, Zhang Tian, Laphanuwat Phatthamon, Bacon Nickolas A, Liu Lijun, Fassl Anne, Sharma Samanta, Otto Tobias, Jecrois Emanuelle, Han Richard, Sweeney Katharine E, Marro Samuele, Wernig Marius, Geng Yan, Moses Alan, Li Cheng, Gygi Steven P, Young Richard A, Sicinski Piotr
机构信息
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Mol Cell. 2020 May 7;78(3):459-476.e13. doi: 10.1016/j.molcel.2020.03.010. Epub 2020 Apr 1.
The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity. We found that in ESCs, a large fraction of Cdk1 substrates is localized on chromatin. Cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. Consistent with these findings, inhibition of Cdk1 altered histone-modification status of ESCs. High levels of Cdk1 in ESCs phosphorylate and partially inactivate Dot1l, the H3K79 methyltransferase responsible for placing activating marks on gene bodies. Decrease of Cdk1 activity during ESC differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ESCs.
细胞周期蛋白依赖性激酶1（Cdk1）驱动细胞分裂。为了揭示Cdk1的其他功能，我们构建了敲入小鼠，使其表达一种模拟敏感型的Cdk1以取代野生型Cdk1。在我们的研究中，我们聚焦于胚胎干细胞（ESC），因为这种细胞类型表现出特别高的Cdk1活性。我们发现，在胚胎干细胞中，很大一部分Cdk1底物定位于染色质上。Cdk1磷酸化许多参与表观遗传调控的蛋白质，包括所有主要组蛋白标记的写入器和擦除器。与这些发现一致，抑制Cdk1会改变胚胎干细胞的组蛋白修饰状态。胚胎干细胞中高水平的Cdk1会磷酸化并部分失活Dot1l，Dot1l是负责在基因体上放置激活标记的H3K79甲基转移酶。在胚胎干细胞分化过程中Cdk1活性的降低会解除对Dot1l的抑制，从而使分化基因得以协调表达。这些分析表明，Cdk1的功能是维持胚胎干细胞的表观遗传特性。
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