scholarly journals The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility

2018 ◽  
Author(s):  
Yiqin Ma ◽  
Daniel J McKay ◽  
Laura Buttitta
Keyword(s):  
Cell Cycle ◽  
Terminal Differentiation ◽  
Chromatin Accessibility ◽  
Cell Cycle Gene ◽  
Cell Cycle Regulators ◽  
Cell Cycle Exit ◽  
Cell Cycle Genes ◽  
Repressor Complex ◽  
Pupal Wing ◽  
A Cell

During terminal differentiation most cells will exit the cell cycle and enter into a prolonged or permanent G0. Cell cycle exit is usually initiated through the repression of cell cycle gene expression by formation of a transcriptional repressor complex called DREAM. However when DREAM repressive function is compromised during terminal differentiation, additional unknown mechanisms act to stably repress cycling and ensure robust cell cycle exit. Here we provide evidence that developmentally programmed, temporal changes in chromatin accessibility at a subset of critical cell cycle genes acts to enforce cell cycle exit during terminal differentiation in the Drosophila melanogaster wing. We show that during terminal differentiation, chromatin closes at a set of pupal wing enhancers for the key rate-limiting cell cycle regulators cycE, e2f1 and stg. This closing coincides with wing cells entering a robust postmitotic state that is strongly refractory to cell cycle re-activation. When cell cycle exit is genetically disrupted, chromatin accessibility at cell cycle genes remains largely unaffected and the closing of enhancers at cycE, e2f1 and stg proceeds independent of the cell cycling status. Instead, disruption of cell cycle exit leads to changes in accessibility and expression of a subset of hormone-induced transcription factors involved in the progression of terminal differentiation. Our results uncover a mechanism that acts as a cell cycle-independent timer to limit aberrant cycling in terminally differentiating tissues. In addition, we provide a new molecular description of the cross-talk between cell cycle exit and terminal differentiation during metamorphosis.

scholarly journals Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to oesophageal adenocarcinoma

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Connor Rogerson ◽  
Samuel Ogden ◽  
Edward Britton ◽  
Yeng Ang ◽  
Andrew D Sharrocks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
Chromatin Accessibility ◽  
Oesophageal Adenocarcinoma ◽  
Cell Cycle Gene ◽  
Molecular Events ◽  
Common Causes ◽  
A Cell

Oesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the molecular events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin to directly regulate cell cycle genes specifically in OAC cells. This new KLF5 target gene programme has potential prognostic significance as high levels correlate with poorer patient survival. Thus, the repurposing of KLF5 for novel regulatory activity in OAC provides new insights into the mechanisms behind disease progression.

scholarly journals Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

2020 ◽  
Author(s):  
Connor Rogerson ◽  
Samuel Ogden ◽  
Edward Britton ◽  
Yeng Ang ◽  
Andrew D. Sharrocks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
Chromatin Accessibility ◽  
Oesophageal Adenocarcinoma ◽  
Cell Cycle Gene ◽  
A Cell

AbstractOesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

scholarly journals In vitro CSC-derived cardiomyocytes exhibit the typical microRNA-mRNA blueprint of endogenous cardiomyocytes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mariangela Scalise ◽  
Fabiola Marino ◽  
Luca Salerno ◽  
Teresa Mancuso ◽  
Donato Cappetta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Terminal Differentiation ◽  
Cell Cycle Regulators ◽  
Cardiomyocyte Differentiation ◽  
Down Regulation ◽  
Cell Cycle Genes ◽  
Neonatal Cardiomyocytes ◽  
Gene Regulatory ◽  
Regulation Of Cell Cycle

AbstractmiRNAs modulate cardiomyocyte specification by targeting mRNAs of cell cycle regulators and acting in cardiac muscle lineage gene regulatory loops. It is unknown if or to-what-extent these miRNA/mRNA networks are operative during cardiomyocyte differentiation of adult cardiac stem/progenitor cells (CSCs). Clonally-derived mouse CSCs differentiated into contracting cardiomyocytes in vitro (iCMs). Comparison of “CSCs vs. iCMs” mRNome and microRNome showed a balanced up-regulation of CM-related mRNAs together with a down-regulation of cell cycle and DNA replication mRNAs. The down-regulation of cell cycle genes and the up-regulation of the mature myofilament genes in iCMs reached intermediate levels between those of fetal and neonatal cardiomyocytes. Cardiomyo-miRs were up-regulated in iCMs. The specific networks of miRNA/mRNAs operative in iCMs closely resembled those of adult CMs (aCMs). miR-1 and miR-499 enhanced myogenic commitment toward terminal differentiation of iCMs. In conclusions, CSC specification/differentiation into contracting iCMs follows known cardiomyo-MiR-dependent developmental cardiomyocyte differentiation trajectories and iCMs transcriptome/miRNome resembles that of CMs.

scholarly journals Genome-Wide Identification and Analysis of Cell Cycle Genes in Birch

Forests ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 120
Author(s):  
Yijie Li ◽  
Song Chen ◽  
Yuhang Liu ◽  
Haijiao Huang
Keyword(s):  
Cell Cycle ◽  
Growth And Development ◽  
Betula Pendula ◽  
Cell Cycle Gene ◽  
Expression Data ◽  
Rna Seq ◽  
Specific Expression ◽  
Cell Cycles ◽  
Cell Cycle Genes ◽  
Genome Wide

Research Highlights: This study identified the cell cycle genes in birch that likely play important roles during the plant’s growth and development. This analysis provides a basis for understanding the regulatory mechanism of various cell cycles in Betula pendula Roth. Background and Objectives: The cell cycle factors not only influence cell cycles progression together, but also regulate accretion, division, and differentiation of cells, and then regulate growth and development of the plant. In this study, we identified the putative cell cycle genes in the B. pendula genome, based on the annotated cell cycle genes in Arabidopsis thaliana (L.) Heynh. It can be used as a basis for further functional research. Materials and Methods: RNA-seq technology was used to determine the transcription abundance of all cell cycle genes in xylem, roots, leaves, and floral tissues. Results: We identified 59 cell cycle gene models in the genome of B. pendula, with 17 highly expression genes among them. These genes were BpCDKA.1, BpCDKB1.1, BpCDKB2.1, BpCKS1.2, BpCYCB1.1, BpCYCB1.2, BpCYCB2.1, BpCYCD3.1, BpCYCD3.5, BpDEL1, BpDpa2, BpE2Fa, BpE2Fb, BpKRP1, BpKRP2, BpRb1, and BpWEE1. Conclusions: By combining phylogenetic analysis and tissue-specific expression data, we identified 17 core cell cycle genes in the Betulapendula genome.

scholarly journals Chromatin organization changes during the establishment and maintenance of the postmitotic state

2017 ◽  
Author(s):  
Yiqin Ma ◽  
Laura Buttitta
Keyword(s):  
Cell Cycle ◽  
Gene Silencing ◽  
Ectopic Expression ◽  
Terminal Differentiation ◽  
Chromatin Organization ◽  
Cell Cycle Exit ◽  
Heterochromatin Protein 1 ◽  
Developmental Potential ◽  
Close Relationship ◽  
The Face

SummaryBackgroundGenome organization changes during development as cells differentiate. Chromatin motion becomes increasingly constrained and heterochromatin clusters as cells become restricted in their developmental potential. These changes coincide with slowing of the cell cycle, which can also influence chromatin organization and dynamics. Terminal differentiation is often coupled with permanent exit from the cell cycle and existing data suggests a close relationship between a repressive chromatin structure and silencing of the cell cycle in postmitotic cells. Here we examine the relationship between chromatin organization, terminal differentiation and cell cycle exit.ResultsWe focused our studies on the Drosophila wing, where epithelial cells transition from active proliferation to a postmitotic state in a temporally controlled manner. We find there are two stages of G0 in this tissue, a flexible G0 period where cells can be induced to re-enter the cell cycle under specific genetic manipulations and a state we call “robust”, where cells become strongly refractory to cell cycle re-entry. Compromising the flexible G0 by driving ectopic expression of cell cycle activators causes a global disruption of the clustering of heterochromatin-associated histone modifications such as H3K27 trimethylation and H3K9 trimethylation, as well as their associated repressors, Polycomb and heterochromatin protein 1(HP1). However, this disruption is reversible. When cells enter a robust G0 state, even in the presence of ectopic cell cycle activity, clustering of heterochromatin associated modifications are restored. If cell cycle exit is bypassed, cells in the wing continue to terminally differentiate, but heterochromatin clustering is severely disrupted. Heterochromatin-dependent gene silencing does not appear to be required for cell cycle exit, as compromising the H3K27 methyltransferase Enhancer of zeste, and/or HP1 cannot prevent the robust cell cycle exit, even in the face of normally oncogenic cell cycle activities.ConclusionsHeterochromatin clustering during terminal differentiation is a consequence of cell cycle exit, rather than differentiation. Compromising heterochromatin-dependent gene silencing does not disrupt cell cycle exit.

scholarly journals Progesterone Increases Rat Neural Progenitor Cell Cycle Gene Expression and Proliferation Via Extracellularly Regulated Kinase and Progesterone Receptor Membrane Components 1 and 2

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3186-3196 ◽  
Author(s):  
Lifei Liu ◽  
Junming Wang ◽  
Liqin Zhao ◽  
Jon Nilsen ◽  
Kelsey McClure ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Progesterone Receptor ◽  
Progenitor Cell ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Mammalian Brain ◽  
Cell Cycle Gene ◽  
Cell Cycle Genes ◽  
Expression Of Genes ◽  
Membrane Components

Progesterone receptor (PR) expression and regulation of neural progenitor cell (NPC) proliferation was investigated using NPC derived from adult rat brain. RT-PCR revealed that PRA mRNA was not detected in rat NPCs, whereas membrane-associated PRs, PR membrane components (PGRMCs) 1 and 2, mRNA were expressed. Progesterone-induced increase in 5-bromo-2-deoxyuridine incorporation was confirmed by fluorescent-activated cell sorting analysis, which indicated that progesterone promoted rat NPC exit of G0/G1 phase at 5 h, followed by an increase in S-phase at 6 h and M-phase at 8 h, respectively. Microarray analysis of cell-cycle genes, real-time PCR, and Western blot validation revealed that progesterone increased expression of genes that promote mitosis and decreased expression of genes that repress cell proliferation. Progesterone-induced proliferation was not dependent on conversion to metabolites and was antagonized by the ERK1/2 inhibitor UO126. Progesterone-induced proliferation was isomer and steroid specific. PGRMC1 small interfering RNA treatment, together with computational structural analysis of progesterone and its isomers, indicated that the proliferative effect of progesterone is mediated by PGRMC1/2. Progesterone mediated NPC proliferation and concomitant regulation of mitotic cell cycle genes via a PGRMC/ERK pathway mechanism is a potential novel therapeutic target for promoting neurogenesis in the mammalian brain.

scholarly journals Genome-Wide Identification and Analysis of Cell Cycle Genes in Betula pendula

2021 ◽  
Author(s):  
Yijie Li ◽  
Song Chen ◽  
Yuhang Liu ◽  
Haijiao Huang
Keyword(s):  
Cell Cycle ◽  
Growth And Development ◽  
Betula Pendula ◽  
Cell Cycle Progression ◽  
Transcript Abundance ◽  
Cell Cycle Gene ◽  
Specific Expression ◽  
Cell Cycles ◽  
Cell Cycle Genes ◽  
Functional Studies

Research Highlights: This study identified the cell cycle genes in birch that likely play important roles during plant growth and development. This analysis provides a basis for understanding the regulatory mechanism of various cell cycles in Betula pendula. Background and Objectives: The cell cycle factors not only influence cell cycle progression together, but also regulate accretion, division and differentiation of cells, and then regulate growth and development of plant. In this study, we identified the putative cell cycle genes in B. pendula genome, based on the annotated cell cycle genes in A. thaliana. It could serve as a foundation for further functional studies. Materials and Methods: The transcript abundance was determined for all the cell cycle genes in xylem, root, leaf and flower tissues using RNA-seq technology. Results: We identified 59 cell cycle gene models in the genome of B. pendula, 17 highly expression genes among them. These genes were BpCDKA.1, BpCDKB1.1, BpCDKB2.1, BpCKS1.2, BpCYCB1.1, BpCYCB1.2, BpCYCB2.1, BpCYCD3.1, BpCYCD3.5, BpDEL1, BpDpa2, BpE2Fa, BpE2Fb, BpKRP1, BpKRP2, BpRb1 and BpWEE1. Conclusions: We identified 17 core cell cycle genes in the genome of birch by combining phylogenetic analysis and tissue specific expression data.

scholarly journals In Vitro CSC-derived Cardiomyocytes Exhibit the Typical microRNA-mRNA Blueprint of Endogenous Cardiomyocytes

2021 ◽  
Author(s):  
Mariangela Scalise ◽  
Fabiola Marino ◽  
Luca Salerno ◽  
Mancuso Teresa ◽  
Donato Cappetta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulators ◽  
Cardiomyocyte Differentiation ◽  
Down Regulation ◽  
Stem Cell Expansion ◽  
Cell Cycle Genes ◽  
Neonatal Cardiomyocytes ◽  
Gene Regulatory ◽  
Regulation Of Cell Cycle

Abstract miRNAs modulate cardiomyocyte specification in embryonic hearts and in pluripotent stem cells by targeting mRNAs of cell cycle regulators and acting in gene regulatory loops that complete commitment to the cardiac muscle lineage. It is still unknown if/to-what-extent these miRNA/mRNA networks are operative during cardiomyocyte differentiation of adult cardiac stem/progenitor cells (CSCs). Clonally-derived mouse CSCs differentiated into contracting cardiomyocytes in vitro (iCMs). RNASeq comparison of “CSCs vs. iCMs” mRNome and microRNome showed a balanced up-regulation of sarcomere and mitochondrial related mRNAs together with a down-regulation of cell cycle and DNA replication mRNAs. The down-regulation of cell cycle genes and the up-regulation of the mature myofilament genes in iCMs did not reach the levels of mouse terminally differentiated adult cardiomyocytes (aCMs), while they get to intermediate levels between those of fetal and neonatal cardiomyocytes. Cardiomyo-miRs were up-regulated in iCMs while those miRs positively regulating stem cell expansion and self-renewal were down-regulated. The specific networks of miRNA/mRNAs operative in iCMs closely resembled miRNA/mRNA networks of aCMs. Two of these miRs, miR-1 and miR-499, enhanced myogenic commitment toward terminal differentiation of iCMs. In conclusions, CSC specification/differentiation into contracting iCMs follows known cardiomyo-MiR-dependent developmental cardiomyocyte differentiation trajectories and iCMs transcriptome/miRNome resembles that of aCMs.

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