scholarly journals Mitotic activity shapes stage-specific histone modification profiles during Xenopus embryogenesis

2020 ◽  
Author(s):  
Daniil Pokrovsky ◽  
Ignasi Forné ◽  
Tobias Straub ◽  
Axel Imhof ◽  
Ralph A.W. Rupp
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Histone Modification ◽  
Cell Fate ◽  
De Novo ◽  
Strong Impact ◽  
Large Set ◽  
Embryo Survival ◽  
Histone Marks ◽  
Epigenetic Information

SummaryForming an embryo from a zygote poses an apparent conflict for epigenetic regulation. On one hand, the de novo induction of cell fate identities requires the establishment and subsequent maintenance of epigenetic information to harnish developmental gene expression. On the other hand, the embryo depends on cell proliferation, and every round of DNA replication dilutes preexisting histone modifications by incorporation of new unmodified histones into chromatin. Here we investigated the possible relationship between the propagation of epigenetic information and the developmental cell proliferation during Xenopus embryogenesis. We systemically inhibited cell proliferation during the G1/S-transition in gastrula embryos and followed their development until the tadpole stage. Comparing wild-type and cell cycle-arrested embryos, we show that the inhibition of cell proliferation is principally compatible with embryo survival and cellular differentiation. In parallel, we quantified by mass spectrometry the abundance of a large set of histone modification states, which reflects the developmental maturation of the embryonic epigenome. The arrested embryos developed abnormal stage-specific histone modification profiles, in which transcriptionally repressive histone marks were overrepresented. Embryos released from the cell cycle block during neurulation reverted back towards normality on morphological, molecular and epigenetic levels. These results indicate that replicational dilution of histone marks has a strong impact on developmental chromatin maturation. We propose that this influence is strong enough to control developmental decisions, specifically in cell populations that switch between resting and proliferating states such as stem cells.

scholarly journals A systemic cell cycle block impacts stage-specific histone modification profiles during Xenopus embryogenesis

PLoS Biology ◽  
2021 ◽  
Vol 19 (9) ◽  
pp. e3001377
Author(s):  
Daniil Pokrovsky ◽  
Ignasi Forné ◽  
Tobias Straub ◽  
Axel Imhof ◽  
Ralph A. W. Rupp
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Histone Modification ◽  
Cell Fate ◽  
De Novo ◽  
Large Set ◽  
Embryo Survival ◽  
Epigenetic Information ◽  
Developmental Gene Expression ◽  
Cell Cycle Block

Forming an embryo from a zygote poses an apparent conflict for epigenetic regulation. On the one hand, the de novo induction of cell fate identities requires the establishment and subsequent maintenance of epigenetic information to harness developmental gene expression. On the other hand, the embryo depends on cell proliferation, and every round of DNA replication dilutes preexisting histone modifications by incorporation of new unmodified histones into chromatin. Here, we investigated the possible relationship between the propagation of epigenetic information and the developmental cell proliferation during Xenopus embryogenesis. We systemically inhibited cell proliferation during the G1/S transition in gastrula embryos and followed their development until the tadpole stage. Comparing wild-type and cell cycle–arrested embryos, we show that the inhibition of cell proliferation is principally compatible with embryo survival and cellular differentiation. In parallel, we quantified by mass spectrometry the abundance of a large set of histone modification states, which reflects the developmental maturation of the embryonic epigenome. The arrested embryos developed abnormal stage-specific histone modification profiles (HMPs), in which transcriptionally repressive histone marks were overrepresented. Embryos released from the cell cycle block during neurulation reverted toward normality on morphological, molecular, and epigenetic levels. These results suggest that the cell cycle block by HUA alters stage-specific HMPs. We propose that this influence is strong enough to control developmental decisions, specifically in cell populations that switch between resting and proliferating states such as stem cells.

scholarly journals Avidin inhibits PHA-induced human peripheral blood mononuclear cell proliferation

2016 ◽  
Vol 25 (1) ◽  
pp. 19-24
Author(s):  
Cicia Firakania ◽  
Indra G. Mansur ◽  
Sri W.A. Jusman ◽  
Mohamad Sadikin
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Peripheral Blood Mononuclear Cell ◽  
Mononuclear Cell ◽  
Peripheral Blood ◽  
De Novo ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Peripheral Blood Mononuclear ◽  
Cell Proliferation Inhibition

Background: Cell proliferation occurs not only in normal but also in cancer cells. Most of cell proliferation inhibition can be done by inhibiting the DNA synthesis, notably by intervening the formation of purine or pyrimidine. In purine de novo synthesis, it was assumed that biotin plays a role as a coenzyme in carboxylation reaction, one of the pivotal steps in the purine de novo pathways. The aim of this study was to see the avidin potency to bind biotin and inhibit mitosis.Methods: Peripheral blood mononuclear cell (PBMC) was cultured in RPMI-1640 medium and stimulated by phytohemagglutinin (PHA) in the presence or absence of interleukin-2 (IL-2), with or without avidin. The effect of avidin addition was observed at 24, 48, and 72 hours for cell proliferation, viability, and cell cycle. Statistical analysis was done by one-way ANOVA.Results: Avidin inhibited cell proliferation and viability in culture under stimulation by PHA with and without IL-2. Cell cycle analysis showed that avidin arrested the progression of PBMC after 72 hours of culture. Most cells were found in G0/G1 phase.Conclusion: Inhibition of biotin utilization by avidin binding can halt cell proliferation.

scholarly journals Shaping of Drosophila Neural Cell Lineages Through Coordination of Cell Proliferation and Cell Fate by the BTB-ZF Transcription Factor Tramtrack-69

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 773-788
Author(s):  
Françoise Simon ◽  
Anne Ramat ◽  
Sophie Louvet-Vallée ◽  
Jérôme Lacoste ◽  
Angélique Burg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Fate ◽  
Zinc Finger ◽  
Molecular Mechanisms ◽  
Neural Cell ◽  
Cell Cycle Exit ◽  
Cell Lineages ◽  
Accessory Cells

Cell diversity in multicellular organisms relies on coordination between cell proliferation and the acquisition of cell identity. The equilibrium between these two processes is essential to assure the correct number of determined cells at a given time at a given place. Using genetic approaches and correlative microscopy, we show that Tramtrack-69 (Ttk69, a Broad-complex, Tramtrack and Bric-à-brac - Zinc Finger (BTB-ZF) transcription factor ortholog of the human promyelocytic leukemia zinc finger factor) plays an essential role in controlling this balance. In the Drosophila bristle cell lineage, which produces the external sensory organs composed by a neuron and accessory cells, we show that ttk69 loss-of-function leads to supplementary neural-type cells at the expense of accessory cells. Our data indicate that Ttk69 (1) promotes cell cycle exit of newborn terminal cells by downregulating CycE, the principal cyclin involved in S-phase entry, and (2) regulates cell-fate acquisition and terminal differentiation, by downregulating the expression of hamlet and upregulating that of Suppressor of Hairless, two transcription factors involved in neural-fate acquisition and accessory cell differentiation, respectively. Thus, Ttk69 plays a central role in shaping neural cell lineages by integrating molecular mechanisms that regulate progenitor cell cycle exit and cell-fate commitment.

scholarly journals Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium

2021 ◽  
Author(s):  
Larissa Mourao ◽  
Amber L. Zeeman ◽  
Katrin E. Wiese ◽  
Anika Bongaarts ◽  
Lieve L. Oudejans ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
De Novo ◽  
Mammary Epithelium ◽  
Mechanistic Explanation ◽  
Tumor Formation ◽  
Epidermal Differentiation ◽  
Cell Proliferation And Differentiation ◽  
Primary Mouse ◽  
Proliferation And Differentiation

In the past forty years, the WNT/CTNNB1 signaling pathway has emerged as a key player in mammary gland development and homeostasis. While also evidently involved in breast cancer, much unclarity continues to surround its precise role in mammary tumor formation and progression. This is largely due to the fact that the specific and direct effects of hyperactive WNT/CTNNB1 signaling on the mammary epithelium remain unknown. Here we use a primary mouse mammary organoid culture system to close this fundamental knowledge gap. We show that hyperactive WNT/CTNNB1 signaling induces competing cell proliferation and differentiation responses. While proliferation is dominant at lower levels of WNT/CTNNB1 signaling activity, higher levels cause reprogramming towards an epidermal cell fate. We show that this involves de novo activation of the epidermal differentiation cluster (EDC) locus and we identify master regulatory transcription factors that likely control the process. This is the first time that the molecular and cellular dose-response effects of WNT/CTNNB1 signaling in the mammary epithelium have been dissected in such detail. Our analyses reveal that the mammary epithelium is exquisitely sensitive to small changes in WNT/CTNNB1 signaling and offer a mechanistic explanation for the squamous differentiation that is observed in some WNT/CTNNB1 driven tumors.

scholarly journals Let-7 regulates cell cycle dynamics in the developing cerebral cortex and retina

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Corinne L. A. Fairchild ◽  
Simranjeet K. Cheema ◽  
Joanna Wong ◽  
Keiko Hino ◽  
Sergi Simó ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Developmental Time ◽  
Neural Progenitors ◽  
Cycle Progression ◽  
Cell Fate Decisions ◽  
Cell Cycle Dynamics

Abstract In the neural progenitors of the developing central nervous system (CNS), cell proliferation is tightly controlled and coordinated with cell fate decisions. Progenitors divide rapidly during early development and their cell cycle lengthens progressively as development advances to eventually give rise to a tissue of the correct size and cellular composition. However, our understanding of the molecules linking cell cycle progression to developmental time is incomplete. Here, we show that the microRNA (miRNA) let-7 accumulates in neural progenitors over time throughout the developing CNS. Intriguingly, we find that the level and activity of let-7 oscillate as neural progenitors progress through the cell cycle by in situ hybridization and fluorescent miRNA sensor analyses. We also show that let-7 mediates cell cycle dynamics: increasing the level of let-7 promotes cell cycle exit and lengthens the S/G2 phase of the cell cycle, while let-7 knock down shortens the cell cycle in neural progenitors. Together, our findings suggest that let-7 may link cell proliferation to developmental time and regulate the progressive cell cycle lengthening that occurs during development.

scholarly journals Identifying Molecular Chechkpoints for Adventitious Root Induction: Are We Ready to Fill the Gaps?

2021 ◽  
Vol 12 ◽  
Author(s):  
Dolores Abarca
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Adventitious Rooting ◽  
Hormonal Control ◽  
Limiting Factors ◽  
Root Induction ◽  
Long Distance

The molecular mechanisms underlying de novo root organogenesis have been under intense study for the last decades. As new tools and resources became available, a comprehensive model connecting the processes and factors involved was developed. Separate phases that allow for specific analyses of individual checkpoints were well defined. Physiological approaches provided information on the importance of metabolic processes and long-distance signaling to balance leaf and stem status and activation of stem cell niches to form new root meristems. The study of plant hormones revealed a series of sequential roles for cytokinin and auxin, dynamically interconnected and modulated by jasmonic acid and ethylene. The identification of genes specifying cell identity uncovered a network of sequentially acting transcriptional regulators that link hormonal control to cell fate respecification. Combined results from herbaceous model plants and the study of recalcitrant woody species underscored the need to understand the limiting factors that determine adventitious rooting competence. The relevance of epigenetic control was emphasized by the identification of microRNAs and chromatin remodeling agents involved in the process. As the different players are set in place and missing pieces become apparent, findings in related processes can be used to identify new candidates to complete the picture. Molecular knobs connecting the balance cell proliferation/differentiation to hormone signaling pathways, transcriptional control of cell fate or metabolic modulation of developmental programs can offer clues to unveil new elements in the dynamics of adventitious rooting regulatory networks. Mechanisms for cell non-autonomous signaling that are well characterized in other developmental processes requiring establishment and maintenance of meristems, control of cell proliferation and cell fate specification can be further explored. Here, we discuss possible candidates and approaches to address or elude the limitations that hinder propagation programs requiring adventitious rooting.

scholarly journals The BTB-ZF transcription factor Tramtrack69 shapes neural cell lineages by coordinating cell proliferation and cell fate

2018 ◽  
Author(s):  
Françoise Simon ◽  
Anne Ramat ◽  
Sophie Louvet-Vallée ◽  
Jérôme Lacoste ◽  
Angélique Burg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Neural Cell ◽  
Cell Cycle Exit ◽  
Cell Lineages ◽  
Accessory Cells

AbstractCell diversity in multicellular organisms relies on coordination between cell proliferation and the acquisition of cell identity. The equilibrium between these two processes is essential to assure the correct number of determined cells at a given time at a given place. Here, we show that Tramtrack-69 (Ttk69, a BTB-ZF transcription factor ortholog of the human PLZF factor) plays an essential role in controlling this balance. In theDrosophilabristle cell lineage, producing the external sensory organs composed by a neuron and accessory cells, we show thatttk69loss of function leads to supplementary neural-type cells at the expense of accessory cells. Our data indicate that Ttk69 (1) promotes cell-cycle exit of newborn terminal cells by downregulatingcycE, the principal cyclin involved in S-phase entry and (2) regulates cell fate acquisition and terminal differentiation by downregulating the expression ofhamletand upregulating that ofSuppressor of Hairless, two transcription factors involved in neural-fate acquisition and accessory-cell differentiation, respectively. Thus, Ttk69 plays a central role in shaping neural cell lineages by integrating molecular mechanisms that regulate progenitor cell-cycle exit and cell-fate commitment.Summary statementTramtrack-69, a transcription factor orthologous to the human tumor-suppressor PLZF, plays a central role in precursor cell lineages by integrating molecular mechanisms that regulate progenitor cell-cycle exit and cell-fate determination.

Effect of insulin on the cell cycle of germinating maize seeds (Zea mays L.)

2013 ◽  
Vol 23 (1) ◽  
pp. 3-14 ◽  
Author(s):  
Alma X. Avila-Alejandre ◽  
Fulgencio Espejel ◽  
Esmeralda Paz-Lemus ◽  
Edith Cortés-Barberena ◽  
Fernando Díaz de León-Sánchez ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Growth Factor ◽  
De Novo ◽  
Bovine Insulin ◽  
Nuclear Antigen ◽  
Insulin Like Growth Factor ◽  
Transcript Accumulation ◽  
Embryonic Axes ◽  
Maize Seeds

AbstractDuring seed germination, metabolism is reactivated, DNA is repaired and cell division is restarted in the meristems. The mechanisms that co-ordinate cell growth and division in maize embryonic axes during germination are not well understood. However, the presence of a factor similar to IGF (insulin-like growth factor) that accelerates germination has been reported. In the present work, the regulation of the cell-cycle restart by bovine insulin [which has been demonstrated to produce similar effects as insulin-like growth factor of maize (ZmIGF) in maize seeds] was studied in germinating embryonic axes. Our results showed that bovine insulin differentially stimulates growth, S6K phosphorylation, S6rp transcript accumulation on the polysomal fraction, as well as de novo DNA synthesis in the radicles and the coleoptiles of the embryonic axis. A stronger and earlier effect was observed in radicles compared to coleoptiles; therefore, the effect of insulin on the cell cycle of the root meristem was studied by flow cytometry. The G1–S transition was stimulated and cell proliferation was induced. Furthermore, it was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) that bovine insulin increased E2F and PCNA (proliferating cell nuclear antigen) transcription after 15 h of germination and PCNA de novo synthesis at 15 h of germination. These results show that bovine insulin preferentially stimulates growth in the radicles of germinating embryonic axes and suggest that its effect on the G1–S transition and the activation of cell proliferation is mediated by the induction of E2F and PCNA transcription.

scholarly journals Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells

2019 ◽  
Author(s):  
Smile Echizenya ◽  
Yukiko Ishii ◽  
Satoshi Kitazawa ◽  
Tadashi Tanaka ◽  
Shun Matsuda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Side Effects ◽  
Cell Cycle Arrest ◽  
Drug Screening ◽  
De Novo ◽  
Pyrimidine Synthesis ◽  
Cycle Arrest ◽  
De Novo Pyrimidine Synthesis ◽  
Essential Enzyme

Abstract Background Glioblastoma-initiating cells (GICs) comprise a tumorigenic subpopulation of cells that are resistant to radio- and chemotherapies and are responsible for cancer recurrence. The aim of this study was to identify novel compounds that specifically eradicate GICs using a high throughput drug screening approach. Methods We performed a cell proliferation/death-based drug screening using 10 560 independent compounds. We identified dihydroorotate dehydrogenase (DHODH) as a target protein of hit compound 10580 using ligand-fishing and mass spectrometry analysis. The medical efficacy of 10580 was investigated by in vitro cell proliferation/death and differentiation and in vivo tumorigenic assays. Results Among the effective compounds, we identified 10580, which induced cell cycle arrest, decreased the expression of stem cell factors in GICs, and prevented tumorigenesis upon oral administration without any visible side effects. Mechanistic studies revealed that 10580 decreased pyrimidine nucleotide levels and enhanced sex determining region Y–box 2 nuclear export by antagonizing the enzyme activity of DHODH, an essential enzyme for the de novo pyrimidine synthesis. Conclusion In this study, we identified 10580 as a promising new drug against GICs. Given that normal tissue cells, in particular brain cells, tend to use the alternative salvage pathway for pyrimidine synthesis, our findings suggest that 10580 can be used for glioblastoma therapy without side effects. Key Points 1.  Chemical screening identified 10580 as a novel GIC-eliminating drug that targets DHODH, an essential enzyme for the de novo pyrimidine synthesis pathway. 2. Compound 10580 induced cell cycle arrest, apoptosis, and differentiation in GICs.

scholarly journals The Krüppel-like factor Cabut has cell cycle regulatory properties similar to E2F1

2021 ◽  
Vol 118 (7) ◽  
pp. e2015675118
Author(s):  
Peng Zhang ◽  
Alexia J. Katzaroff ◽  
Laura A. Buttitta ◽  
Yiqin Ma ◽  
Huaqi Jiang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Cyclin E ◽  
Intestinal Stem Cell ◽  
Cell Cycle Gene ◽  
Large Set ◽  
Gene Promoters ◽  
Cell Divisions ◽  
Stem Cell Divisions

Using a gain-of-function screen in Drosophila, we identified the Krüppel-like factor Cabut (Cbt) as a positive regulator of cell cycle gene expression and cell proliferation. Enforced cbt expression is sufficient to induce an extra cell division in the differentiating fly wing or eye, and also promotes intestinal stem cell divisions in the adult gut. Although inappropriate cell proliferation also results from forced expression of the E2f1 transcription factor or its target, Cyclin E, Cbt does not increase E2F1 or Cyclin E activity. Instead, Cbt regulates a large set of E2F1 target genes independently of E2F1, and our data suggest that Cbt acts via distinct binding sites in target gene promoters. Although Cbt was not required for cell proliferation during wing or eye development, Cbt is required for normal intestinal stem cell divisions in the midgut, which expresses E2F1 at relatively low levels. The E2F1-like functions of Cbt identify a distinct mechanism for cell cycle regulation that may be important in certain normal cell cycles, or in cells that cycle inappropriately, such as cancer cells.

Sign in / Sign up

Export Citation Format

Share Document