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Mammalian CDC14 phosphatases control bivalent promoters and exit from stemness in pluripotent cells [snGEX]

ABSTRACT: CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b -null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells, and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1) during the exit from stemness. Multiomic single-cell analysis of differentiating ESCs suggest that increased UTF1 levels in the absence of CDC14 prevent the firing of bivalent promoters required for differentiation. These results, along recent data suggesting a critical role for cell cycle kinases in pluripotency, suggest that cell cycle kinase-phosphatase modules such as CDK-CDC14 are critical for linking cell cycle regulation and self-renewal, with a specific function for CDC14 phosphatases modulating key epigenetic regulators during the terminal exit from pluripotency.

ORGANISM(S): Mus musculus

PROVIDER: GSE196139 | GEO | 2022/10/31

REPOSITORIES: GEO

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Mammalian CDC14 phosphatases control bivalent promoters and exit from stemness in pluripotent cells [snATAC-Seq]

Project description:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b -null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells, and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1) during the exit from stemness. Multiomic single-cell analysis of differentiating ESCs suggest that increased UTF1 levels in the absence of CDC14 prevent the firing of bivalent promoters required for differentiation. These results, along recent data suggesting a critical role for cell cycle kinases in pluripotency, suggest that cell cycle kinase-phosphatase modules such as CDK-CDC14 are critical for linking cell cycle regulation and self-renewal, with a specific function for CDC14 phosphatases modulating key epigenetic regulators during the terminal exit from pluripotency.

2022-10-31 | GSE196137 | GEO

Mammalian CDC14 control differentiation from pluripotent cells by modulating UTF1 activity on bivalent promoters

Project description:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b-null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. During ESC differentiation, CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1), a critical regulator of stemness. In the absence of CDC14, increased UTF1 levels prevent the firing of bivalent promoters, resulting in defective induction of the transcriptional programs required for differentiation. These results suggest that mammalian CDC14 phosphatases function during the terminal exit from the cell cycle by modulating the transition from the pluripotent to the differentiated chromatin state, at least partially by controlling chromatin dynamics and transcription in a UTF1-dependent manner.

2022-10-31 | GSE191197 | GEO

Mammalian CDC14 control differentiation from pluripotent cells by modulating UTF1 activity on bivalent promoters

Project description:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b-null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. During ESC differentiation, CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1), a critical regulator of stemness. In the absence of CDC14, increased UTF1 levels prevent the firing of bivalent promoters, resulting in defective induction of the transcriptional programs required for differentiation. These results suggest that mammalian CDC14 phosphatases function during the terminal exit from the cell cycle by modulating the transition from the pluripotent to the differentiated chromatin state, at least partially by controlling chromatin dynamics and transcription in a UTF1-dependent manner.

2022-10-31 | PXD030296 | Pride

Regulation of pluripotency and self-renewal of ES cells through epigenetic-threshold modulation and mRNA pruning

Project description:The core pluripotency factors (Oct4, Sox2, and Nanog), the Myc network, and the chromatin-modifying complexes such as PRC2 ensure the pluripotency and self-renewal of ES cells (ESC). How these factors coordinate with one another remains poorly understood. We report that Utf1, a target of Oct4 and Sox2, is a new bivalent chromatin component that buffers poised states of bivalent genes. By limiting PRC2 loading and Histone 3 lysine-27 trimethylation, Utf1 sets proper activation thresholds for bivalent genes. It also promotes nuclear tagging of mRNAs transcribed from insufficiently silenced bivalent genes for cytoplasmic degradation through mRNA de-capping. Whereas these opposing functions of Utf1 allow proper execution of ESC pluripotency, the mRNA pruning function also ensures rapid cell proliferation by blocking the Myc-Arf feedback regulation. Thus, Utf1 is an important regulator that couples the core pluripotency factors with Myc and PRC2 networks to promote proliferation and pluripotency execution of ESCs. First we mapped Utf1 binding sites in ESCs using the biotin-mediated and cross-linked ChIP-sequencing. To investigate how Utf1 might regulate gene expression, we did RNA-seq on WT and Utf1-KO ES cells. Then we did ChIP-seq of Suz12 and H3K27me3 on WT and Utf1-KO ES cells to study whether Utf1 affects PRC2 loading and H3K27me3 modofication, using H3 as control. Finally, we did RNAseq on WT and Dcp1a-KD ES cells to confirm Utf1 repress gene expression by recruiting Dcp1a complex.

2012-10-26 | E-GEOD-39513 | biostudies-arrayexpress

Human Cdc14A is phosphorylated by Cdk1 at early mitosis

Project description:Cdc14 enzymes compose a family of highly conserved phosphatases that are present in a wide range of organisms, including yeast and humans, and that preferentially reverse the phosphorylation of Cyclin-Dependent Kinase (Cdk) substrates. The budding yeast Cdc14 orthologue has essential functions in the control of late mitosis and cytokinesis. In mammals, however, the two Cdc14 homologues, Cdc14A and Cdc14B, do not play a prominent role in controlling late mitotic events, suggesting that some Cdc14 functions are not conserved across species. Moreover, in yeast, Cdc14 is regulated by changes in its subcellular location and by phosphorylation events. In contrast, little is known about the regulation of human Cdc14 phosphatases. Here, we have studied how the human Cdc14A orthologue is regulated during the cell cycle. We found that Cdc14A is phosphorylated on Ser411, Ser453 and Ser549 by Cdk1 early in mitosis and becomes dephosphorylated during late mitotic stages. Interestingly, in vivo and in vitro experiments revealed that, unlike in yeast, Cdk1-mediated phosphorylation of human Cdc14A did not control its catalytic activity but likely modulated its interaction with other proteins in early mitosis. These findings point to differences in Cdk1-mediated mechanisms of regulation between human and yeast Cdc14 orthologues.

2018-08-13 | PXD009481 | Pride

Regulation of pluripotency and self-renewal of ES cells through epigenetic-threshold modulation and mRNA pruning

2012-10-26 | GSE39513 | GEO

Cdc14 and PP2A Phosphatases Cooperate to Shape Phosphoproteome Dynamics during Mitotic Exit

Project description:Temporal control over protein phosphorylation and dephosphorylation is crucial for accurate chromosome segregation and for completion of the cell division cycle during exit from mitosis. In budding yeast, the Cdc14 phosphatase is thought to be a major regulator at this time, while in higher eukaryotes PP2A phosphatases take a dominant role. Here, we use time-resolved phosphoproteome analysis in budding yeast to evaluate the respective contributions of Cdc14 and the two main PP2A isoforms, PP2A(Cdc55) and PP2A(Rts1). This reveals an overlapping requirement for all three phosphatases during mitotic progression. Cdc14 instructs the sequential pattern of phosphorylation changes, in part through its preferential recognition of serine-based cyclin-dependent kinase (Cdk) substrates. PP2A(Cdc55) and PP2A(Rts1) in turn exhibit a broad substrate spectrum with some selectivity for phospho-threonines and a role for PP2A(Rts1) in sustaining Aurora kinase activity. Our results illustrate synergy and coordination between phosphatases as they orchestrate phosphoproteome dynamics during mitotic progression.

2019-11-12 | PXD012860 | Pride

Protein Phosphatase 1 regulates atypical chromosome segregation and cell polarity during mitotic and meiotic division in Plasmodium sexual stages

Project description:PP1 is a conserved serine/threonine phosphatase that regulates many aspects of mitosis and meiosis, often working in concert with other phosphatases, such as CDC14 and CDC25, in model eukaryotes. However, the malaria parasite, Plasmodium spp. lacks the CDC14 and CDC25 genes. The proliferative stages of the parasite life cycle include sexual development within the mosquito vector, with male gamete formation characterized by an atypical rapid mitosis, with three rounds of DNA synthesis, successive spindle formation with clustered kinetochore, and a meiotic stage during zygote to ookinete development following fertilization. It is unclear how PP1 is involved these unusual processes. Using real-time live-cell imaging, conditional gene knockdown, RNAseq and proteomic approaches, we show that Plasmodium PP1 is involved in both chromosome segregation during mitotic exit, and establishment of cell polarity during these sexual stages, suggesting that PP1 inhibitors may block parasite transmission.

2021-07-08 | GSE164175 | GEO

Cdc14 as transcription regulator of RNA pol-II

Project description:In yeast, the phosphatase Cdc14 is required for mitotic exit and for segregation of repetitive regions. Cdc14 is also a subunit of the silencing complex RENT, but no roles in transcription repression have been described. Here we report that Cdc14 promotes silencing at the integenic spacer sequences (IGS) of ribosomal genes during interphase and at Y' repeats in sub-telomeric regions during mitosis, through its ability to dephosphotylate the CDT domain of the RNA polymerase II. CDC14 and CDC15 strains were grown at 25Â°C and 37Â°C. Comparisons were made between each strain at different temperatures, and between strains at the same temperature.

2011-07-28 | E-GEOD-31020 | biostudies-arrayexpress

Snf1 is involved in the aberrant cell cycle induction in cdc14-3 mutant upon NaCl stress in S. cerevisiae

Project description:Transcriptome profiling of cdc14-3 and cdc14-3_snf1 mutants at non-permissive temp (35C) for 90min or 2hr followed by 30min NaCl stress. The experiment showed the aberrant cell cycle induction in cdc14-3 mutants upon NaCl response is abrogated with snf1 deletion in cdc14-3 background.

2014-12-03 | GSE56995 | GEO

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