Gcn5-mediated acetylation at MBF-regulated promoters induces the G1/S transcriptional wave

Abstract In fission yeast, MBF-dependent transcription is inactivated at the end of S phase through a negative feedback loop that involves the co-repressors, Yox1 and Nrm1. Although this repression system is well known, the molecular mechanisms involved in MBF activation remain largely unknown. Compacted chromatin constitutes a barrier to activators accessing promoters. Here, we show that chromatin regulation plays a key role in activating MBF-dependent transcription. Gcn5, a part of the SAGA complex, binds to MBF-regulated promoters through the MBF co-activator Rep2 in a cell cycle-dependent manner and in a reverse correlation to the binding of the MBF co-repressors, Nrm1 or Yox1. We propose that the co-repressors function as physical barriers to SAGA recruitment onto MBF promoters. We also show that Gcn5 acetylates specific lysine residues on histone H3 in a cell cycle-regulated manner. Furthermore, either in a gcn5 mutant or in a strain in which histone H3 is kept in an unacetylated form, MBF-dependent transcription is downregulated. In summary, Gcn5 is required for the full activation and correct timing of MBF-regulated gene transcription.

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Ser68 phosphoregulation is essential for CENP-A deposition, centromere function and viability in mice

10.1101/2021.11.23.469796 ◽

2021 ◽

Author(s):

Yuting Liu ◽

Kehui Wang ◽

Li Huang ◽

Jicheng Zhao ◽

Xinpeng Chen ◽

...

Keyword(s):

Cell Cycle ◽

Cell Viability ◽

Histone H3 ◽

Dependent Manner ◽

Centromere Function ◽

Histone H3 Variant ◽

A Cell ◽

Cycle Dependent ◽

Spatiotemporal Control

Centromere identity is defined by nucleosomes containing CENP-A, a histone H3 variant. The deposition of CENP-A at centromeres is tightly regulated in a cell-cycle-dependent manner. We previously reported that the spatiotemporal control of centromeric CENP-A incorporation is mediated by the phosphorylation of CENP-A Ser68. However, a recent report argued that Ser68 phosphoregulation is dispensable for accurate CENP-A loading. Here, we report that the substitution of Ser68 of endogenous CENP-A with either Gln68 or Glu68 severely impairs CENP-A deposition and cell viability. We also find that mice harboring the corresponding mutations are lethal. Together, these results indicate that the dynamic phosphorylation of Ser68 ensures cell-cycle-dependent CENP-A deposition and cell viability.

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Gains of 12p13.31 delay WNT-mediated initiation of hPSC differentiation and promote residual pluripotency in a cell cycle dependent manner

10.1101/2021.05.22.445238 ◽

2021 ◽

Author(s):

Alexander Keller ◽

Yingnan Lei ◽

Nuša Krivec ◽

Edouard Couvreu De Deckersberg ◽

Dominika Dziedzicka ◽

...

Keyword(s):

Cell Cycle ◽

Wnt Signaling ◽

Feedback Loop ◽

Molecular Mechanisms ◽

Physical Interaction ◽

Dependent Manner ◽

Pluripotent Cells ◽

Primary Driver ◽

A Cell ◽

Cycle Dependent

Though gains of chromosome 12p13.31 are highly recurrent in hPSC, their impact on differentiation is poorly understood. We identify a reduction in differentiation capacity towards all three germ layers and a subpopulation of residual pluripotent cells that appear during hepatic specification. These cells form as a result of the overexpression of NANOG and GDF3, whereby NANOG as the primary driver delays activation of WNT signaling, partly as a result of a direct physical interaction with TCF7. Entry into the residual state is determined by cell cycle position at the onset of differentiation and is maintained by a feedback loop between NANOG and GDF3. These findings highlight the ability of genetically abnormal hPSC to escape correct differentiation and to form residual pluripotent cells, an important risk in the safe clinical translation of hPSC. Our results further refine the molecular mechanisms that underpin the exit from pluripotency and onset of differentiation.

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The PHLPP1 N-Terminal Extension is a Mitotic Cdk1 Substrate and Controls an Interactome Switch

Molecular and Cellular Biology ◽

10.1128/mcb.00333-20 ◽

2021 ◽

Author(s):

Agnieszka T. Kawashima ◽

Cassandra Wong ◽

Gema Lordén ◽

Charles C. King ◽

Pablo Lara-Gonzalez ◽

...

Keyword(s):

Cell Cycle ◽

Molecular Mechanisms ◽

Protein Phosphatase 1 ◽

Dependent Manner ◽

Ph Domain ◽

Chromosomal Segregation ◽

A Cell ◽

Cycle Dependent ◽

Tumor Suppressive Function ◽

Leucine Rich Repeat Protein

PH domain Leucine-Rich Repeat Protein Phosphatase 1 (PHLPP1) is a tumor suppressor that directly dephosphorylates a wide array of substrates, most notably the pro-survival kinase Akt. However, little is known about the molecular mechanisms governing PHLPP1 itself. Here we report that PHLPP1 is dynamically regulated in a cell cycle-dependent manner, and deletion of PHLPP1 results in mitotic delays and increased rates of chromosomal segregation errors. We show that PHLPP1 is hyperphosphorylated during mitosis by Cdk1 in a functionally uncharacterized region known as the PHLPP1 N-terminal extension (NTE). A proximity-dependent biotin identification (BioID) interaction screen revealed that during mitosis PHLPP1 dissociates from plasma membrane scaffolds, such as Scribble, by a mechanism that depends on its NTE, and gains proximity with kinetochore and mitotic spindle proteins such as KNL1 and TPX2. Our data are consistent with a model in which phosphorylation of PHLPP1 during mitosis regulates binding to its mitotic partners and allows accurate progression through mitosis. The finding that PHLPP1 binds mitotic proteins in a cell cycle- and phosphorylation-dependent manner may have relevance to its tumor suppressive function.

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Truncated APC regulates the transcriptional activity of β-catenin in a cell cycle dependent manner

Human Molecular Genetics ◽

10.1093/hmg/ddl464 ◽

2006 ◽

Vol 16 (2) ◽

pp. 199-209 ◽

Cited By ~ 38

Author(s):

Jean Schneikert ◽

Annette Grohmann ◽

Jürgen Behrens

Keyword(s):

Cell Cycle ◽

Transcriptional Activity ◽

Dependent Manner ◽

A Cell ◽

Cycle Dependent

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The Epigenetic Repertoire of Daphnia magna Includes Modified Histones

Genetics Research International ◽

10.1155/2012/174860 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

Nicole F. Robichaud ◽

Jeanette Sassine ◽

Margaret J. Beaton ◽

Vett K. Lloyd

Keyword(s):

Life Cycle ◽

Histone H3 ◽

Dependent Manner ◽

Nurse Cells ◽

Important Species ◽

Clonal Population ◽

A Cell ◽

Cycle Dependent

Daphnids are fresh water microcrustaceans, many of which follow a cyclically parthenogenetic life cycle. Daphnia species have been well studied in the context of ecology, toxicology, and evolution, but their epigenetics remain largely unexamined even though sex determination, the production of sexual females and males, and distinct adult morphological phenotypes, are determined epigenetically. Here, we report on the characterization of histone modifications in Daphnia. We show that a number of histone H3 and H4 modifications are present in Daphnia embryos and histone H3 dimethylated at lysine 4 (H3K4me2) is present nonuniformly in the nucleus in a cell cycle-dependent manner. In addition, this histone modification, while present in blastula and gastrula cells as well as the somatic cells of adults, is absent or reduced in oocytes and nurse cells. Thus, the epigenetic repertoire of Daphnia includes modified histones and as these epigenetic forces act on a genetically homogeneous clonal population Daphnia offers an exceptional tool to investigate the mechanism and role of epigenetics in the life cycle and development of an ecologically important species.

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Correction: Optineurin Regulates the Interferon Response in a Cell Cycle-Dependent Manner

PLoS Pathogens ◽

10.1371/journal.ppat.1004971 ◽

2015 ◽

Vol 11 (6) ◽

pp. e1004971 ◽

Cited By ~ 5

Author(s):

Pierre Génin ◽

Frédérique Cuvelier ◽

Sandrine Lambin ◽

Josina Côrte-Real Filipe ◽

Elodie Autrusseau ◽

...

Keyword(s):

Cell Cycle ◽

Interferon Response ◽

Dependent Manner ◽

A Cell ◽

Cycle Dependent

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Cell Cycle Association of the Retinoblastoma Protein Rb and the Histone Demethylase LSD1 with the Epstein-Barr Virus Latency Promoter Cp

Journal of Virology ◽

10.1128/jvi.01412-07 ◽

2008 ◽

Vol 82 (7) ◽

pp. 3428-3437 ◽

Cited By ~ 23

Author(s):

Charles M. Chau ◽

Zhong Deng ◽

Hyojueng Kang ◽

Paul M. Lieberman

Keyword(s):

Cell Cycle ◽

Epstein Barr Virus ◽

Affinity Purification ◽

Histone H3 ◽

Histone Demethylase ◽

Stable Complex ◽

Dependent Manner ◽

Barr Virus ◽

A Cell ◽

Epstein Barr

ABSTRACT The Epstein-Barr virus C promoter (Cp) regulates the major multicistronic transcript encoding the EBNA-LP, 1, 2, and 3 genes required for B-cell proliferation during latency. The growth-transforming potential of these viral genes suggests that they must be tightly regulated with the host cell cycle and differentiation process. To better understand Cp regulation, we used DNA affinity purification to identify cellular and viral proteins that bind to Cp in latently infected cells. Several previously unknown factors were identified, including the cell cycle regulatory proteins E2F1 and Rb. E2F1 bound to a specific site in Cp located in the core Cp region 3′ of the known EBNA2-responsive RBP-Jk (CSL, CBF1) binding site. The histone H3 K4 demethylase LSD1 (BCC110) was also identified by DNA affinity and was shown to form a stable complex with Rb. Coimmunoprecipitation assays demonstrated that E2F1, Rb, and LSD1 bind to Cp in a cell cycle-dependent manner. Rb and LSD1 binding to Cp increased after the S phase, corresponding to a decrease in histone H3 K4 methylation and Cp transcription. Coimmunoprecipitation and immunofluorescence assays reveal that LSD1 interacts with Rb. Surprisingly, LSD1 did not coimmunoprecipitate with E2F1, suggesting that it associates with Rb independently of E2F1. Depletion of LSD1 by small interfering RNAs inhibited Cp basal transcription levels, and overexpression of LSD1 altered the cell cycle profile in p53-positive (p53+), but not p53-negative (p53−), HCT cells. These findings indicate that Cp is a cell cycle-regulated promoter that is under the control of Rb and the histone demethylase LSD1 in multiple latency types.

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