Cdk1 Controls Global Epigenetic Landscape in Embryonic Stem Cells

Michowski, Wojciech; Chick, Joel M.; Chu, Chengcai; Kołodziejczyk, Aleksandra S.; Wang, Yichen; Suski, Jan M.; Abraham, Brian J.; Anders, Lars; Day, Daniel S.; Dunkl, Lukas Manuel; Man, Mitchell Li Cheong; Zhang, Tian; Laphanuwat, Phatthamon; Bacon, Nickolas A.; Liu, Lijun; Fassl, Anne; Sharma, Samanta; Otto, Tobias; Jecrois, Emanuelle; Han, Richard C.; Sweeney, Katharine E.; Marro, Samuele; Wernig, Marius; Geng, Yan; Moses, Alan M.; Li, Cheng; Gygi, Steven P.; Young, Richard A.; Siciński, Piotr

doi:10.1016/j.molcel.2020.03.010

Cited by 94 publications

(108 citation statements)

References 97 publications

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“…A total of 2.5 μM CDK1i blocked the induction of CCNB1 but not CDC25B or CCNA2 in A549 cells ( Figure 7E ) and significantly reduced the induction of CCNB1 and CCNA2 but not CDC25B in the more sensitive H460 cells ( Figure S5H ). The differential effect of CDK1i on these MMB-FOXM1 target genes could reflect the differing number of CHR motifs in the gene promoters ( Fischer et al, 2016 ) or the recently identified regulation of epigenetic factors by CDK1 ( Michowski et al, 2020 ). The consistent result is that CDK1 activity remaining after 2.5 μM CDK1i was sufficient to block CHK1i-induced MMB-FOXM1 activity and increased expression of CCNB1, the mitotic activator of CDK1, during S phase.…”

Section: Resultsmentioning

confidence: 99%

MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity

et al. 2021

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SUMMARY To identify genes whose loss confers resistance to CHK1 inhibitors, we perform genome-wide CRISPR-Cas9 screens in non-small-cell lung cancer (NSCLC) cell lines treated with the CHK1 inhibitor prexasertib (CHK1i). Five of the top six hits of the screens, MYBL2 (B-MYB), LIN54, FOXM1, cyclin A2 (CCNA2), and CDC25B, are cell-cycle-regulated genes that contribute to entry into mitosis. Knockout of MMB-FOXM1 complex components LIN54 and FOXM1 reduce CHK1i-induced DNA replication stress markers and premature mitosis during Late S phase. Activation of a feedback loop between the MMB-FOXM1 complex and CDK1 is required for CHK1i-induced premature mitosis in Late S phase and subsequent replication catastrophe, indicating that dysregulation of the S to M transition is necessary for CHK1 inhibitor sensitivity. These findings provide mechanistic insights into small molecule inhibitors currently studied in clinical trials and provide rationale for combination therapies.

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Section: Resultsmentioning

confidence: 99%

MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity

et al. 2021

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“…Secondly, our data show that H3K79me2 increases globally during neuronal differentiation in vitro. Michowski et al 46 have recently shown that DOT1L localization and activity is controlled by CDK1 in mESC, causing global epigenetic effects during differentiation. The proposed mechanism is consistent with the global H3K79me2 increase that we observe during neuronal differentiation.…”

Section: Discussionmentioning

confidence: 99%

DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility

et al. 2020

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During neuronal differentiation, the transcriptional profile and the epigenetic context of neural committed cells is subject to significant rearrangements, but a systematic quantification of global histone modification changes is still missing. Here, we show that H3K79me2 increases and H3K27ac decreases globally during in-vitro neuronal differentiation of murine embryonic stem cells. DOT1L mediates all three degrees of methylation of H3K79 and its enzymatic activity is critical to modulate cellular differentiation and reprogramming. In this context, we find that inhibition of DOT1L in neural progenitor cells biases the transcriptional state towards neuronal differentiation, resulting in transcriptional upregulation of genes marked with H3K27me3 on the promoter region. We further show that DOT1L inhibition affects accessibility of SOX2-bound enhancers and impairs SOX2 binding in neural progenitors. Our work provides evidence that DOT1L activity gates differentiation of progenitors by allowing SOX2-dependent transcription of stemness programs.

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“…For instance, CDK1, a candidate gene in our list, phosphorylates several proteins, including MLL2, LSD1, G9a, SUV39H2, SETD2, DOT1L, p300, KDM2A, and HDAC6, involved in histone modifications and transcription regulation. Besides, DNA maintenance methyltransferase (DNMT1) and the proteins that reverse DNA methylation, i.e., Tet1 and Tet2, are also phosphorylated by CDK1 ( Michowski et al, 2020 ). Additionally, the identification of cell cycle regulators in our screen ( Figure 1B and Supplementary Table 1 ) supports the notion that PcG/trxG system is regulated in a cell cycle dependent manner ( Laprell et al, 2017 ; Asenjo et al, 2020 ), which may play a role in faithful inheritance of epigenetic states across cell divisions.…”

Section: Discussionmentioning

confidence: 99%

Kinome-Wide RNAi Screen Uncovers Role of Ballchen in Maintenance of Gene Activation by Trithorax Group in Drosophila

Khan

Akhtar

Umer

et al. 2021

Front. Cell Dev. Biol.

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Polycomb group (PcG) and trithorax group (trxG) proteins are evolutionary conserved factors that contribute to cell fate determination and maintenance of cellular identities during development of multicellular organisms. The PcG maintains heritable patterns of gene silencing while trxG acts as anti-silencing factors by conserving activation of cell type specific genes. Genetic and molecular analysis has revealed extensive details about how different PcG and trxG complexes antagonize each other to maintain cell fates, however, the cellular signaling components that contribute to the preservation of gene expression by PcG/trxG remain elusive. Here, we report an ex vivo kinome-wide RNAi screen in Drosophila aimed at identifying cell signaling genes that facilitate trxG in counteracting PcG mediated repression. From the list of trxG candidates, Ballchen (BALL), a histone kinase known to phosphorylate histone H2A at threonine 119 (H2AT119p), was characterized as a trxG regulator. The ball mutant exhibits strong genetic interactions with Polycomb (Pc) and trithorax (trx) mutants and loss of BALL affects expression of trxG target genes. BALL co-localizes with Trithorax on chromatin and depletion of BALL results in increased H2AK118 ubiquitination, a histone mark central to PcG mediated gene silencing. Moreover, BALL was found to substantially associate with known TRX binding sites across the genome. Genome wide distribution of BALL also overlaps with H3K4me3 and H3K27ac at actively transcribed genes. We propose that BALL mediated signaling positively contributes to the maintenance of gene activation by trxG in counteracting the repressive effect of PcG.

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Cdk1 Controls Global Epigenetic Landscape in Embryonic Stem Cells

Cited by 94 publications

References 97 publications

MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity

MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity

DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility

Kinome-Wide RNAi Screen Uncovers Role of Ballchen in Maintenance of Gene Activation by Trithorax Group in Drosophila

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