scholarly journals Transcriptome analysis of tetraploid cells identifies cyclin D2 as a facilitator of adaptation to genome doubling in the presence of p53

2016 ◽  
Vol 27 (20) ◽  
pp. 3065-3084 ◽  
Author(s):  
Tamara A. Potapova ◽  
Christopher W. Seidel ◽  
Andrew C. Box ◽  
Giulia Rancati ◽  
Rong Li
Keyword(s):  
Gene Expression ◽  
Transcriptome Analysis ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Single Cells ◽  
Cyclin D2 ◽  
Genome Doubling ◽  
Polyploid Cells ◽  
Diploid Cells ◽  
P53 Target Genes

Tetraploidization, or genome doubling, is a prominent event in tumorigenesis, primarily because cell division in polyploid cells is error-prone and produces aneuploid cells. This study investigates changes in gene expression evoked in acute and adapted tetraploid cells and their effect on cell-cycle progression. Acute polyploidy was generated by knockdown of the essential regulator of cytokinesis anillin, which resulted in cytokinesis failure and formation of binucleate cells, or by chemical inhibition of Aurora kinases, causing abnormal mitotic exit with formation of single cells with aberrant nuclear morphology. Transcriptome analysis of these acute tetraploid cells revealed common signatures of activation of the tumor-suppressor protein p53. Suppression of proliferation in these cells was dependent on p53 and its transcriptional target, CDK inhibitor p21. Rare proliferating tetraploid cells can emerge from acute polyploid populations. Gene expression analysis of single cell–derived, adapted tetraploid clones showed up-regulation of several p53 target genes and cyclin D2, the activator of CDK4/6/2. Overexpression of cyclin D2 in diploid cells strongly potentiated the ability to proliferate with increased DNA content despite the presence of functional p53. These results indicate that p53-mediated suppression of proliferation of polyploid cells can be averted by increased levels of oncogenes such as cyclin D2, elucidating a possible route for tetraploidy-mediated genomic instability in carcinogenesis.

scholarly journals Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression

Oncogene ◽  
2003 ◽  
Vol 22 (23) ◽  
pp. 3645-3654 ◽  
Author(s):  
Asra Mirza ◽  
Qun Wu ◽  
Luquan Wang ◽  
Terri McClanahan ◽  
W Robert Bishop ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Transcriptional Program ◽  
Cycle Progression ◽  
P53 Target Genes

scholarly journals Transcriptome analysis of a barley breeding program examines gene expression diversity and reveals target genes for malting quality improvement

BMC Genomics ◽  
2010 ◽  
Vol 11 (1) ◽  
Author(s):  
María Muñoz-Amatriaín ◽  
Yanwen Xiong ◽  
Mark R Schmitt ◽  
Hatice Bilgic ◽  
Allen D Budde ◽  
...  
Keyword(s):  
Gene Expression ◽  
Quality Improvement ◽  
Transcriptome Analysis ◽  
Target Genes ◽  
Breeding Program ◽  
Malting Quality ◽  
Barley Breeding

scholarly journals E2f1, E2f2, and E2f3 Control E2F Target Expression and Cellular Proliferation via a p53-Dependent Negative Feedback Loop

2007 ◽  
Vol 27 (1) ◽  
pp. 65-78 ◽  
Author(s):  
Cynthia Timmers ◽  
Nidhi Sharma ◽  
Rene Opavsky ◽  
Baidehi Maiti ◽  
Lizhao Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Cyclin Dependent Kinase ◽  
Control Of Gene Expression ◽  
Target Gene Expression ◽  
Rb Phosphorylation ◽  
P53 Target Genes

ABSTRACT E2F-mediated control of gene expression is believed to have an essential role in the control of cellular proliferation. Using a conditional gene-targeting approach, we show that the targeted disruption of the entire E2F activator subclass composed of E2f1, E2f2, and E2f3 in mouse embryonic fibroblasts leads to the activation of p53 and the induction of p53 target genes, including p21 CIP1 . Consequently, cyclin-dependent kinase activity and retinoblastoma (Rb) phosphorylation are dramatically inhibited, leading to Rb/E2F-mediated repression of E2F target gene expression and a severe block in cellular proliferation. Inactivation of p53 in E2f1-, E2f2-, and E2f3-deficient cells, either by spontaneous mutation or by conditional gene ablation, prevented the induction of p21 CIP1 and many other p53 target genes. As a result, cyclin-dependent kinase activity, Rb phosphorylation, and E2F target gene expression were restored to nearly normal levels, rendering cells responsive to normal growth signals. These findings suggest that a critical function of the E2F1, E2F2, and E2F3 activators is in the control of a p53-dependent axis that indirectly regulates E2F-mediated transcriptional repression and cellular proliferation.

scholarly journals Induction of Mxi1-SRα by FOXO3a Contributes to Repression of Myc-Dependent Gene Expression

2007 ◽  
Vol 27 (13) ◽  
pp. 4917-4930 ◽  
Author(s):  
Oona Delpuech ◽  
Beatrice Griffiths ◽  
Philip East ◽  
Abdelkader Essafi ◽  
Eric W.-F. Lam ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle Progression ◽  
Dna Microarrays ◽  
Target Genes ◽  
Gene Activation ◽  
Transcriptional Response ◽  
Inhibitory Effect ◽  
Pi3 Kinase ◽  
Promoter Regions ◽  
Inhibition Of Proliferation

ABSTRACT Forkhead transcription factors of the O class (FOXOs) are important targets of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. FOXOs have been implicated in the regulation of cell cycle progression, oxidative stress resistance, and apoptosis. Using DNA microarrays, we analyzed the transcriptional response to FOXO3a activation by gene expression analysis in DLD-1 colon cancer cells stably expressing a FOXO3a.A3-ER fusion protein. We found that activation of FOXO3a resulted in repression of a number of previously identified Myc target genes. Furthermore, FOXO3a activation induced expression of several members of the Mad/Mxd family of transcriptional repressors, most notably Mxi1. The induction of Mxi1 by FOXO3a was specific to the Mxi1-SRα isoform and was mediated by three highly conserved FOXO binding sites within the first intron of the gene. Activation of FOXO3a in response to inhibition of Akt also resulted in activation of Mxi1-SRα expression. Silencing of Mxi1 by small interfering RNA (siRNA) reduced FOXO3a-mediated repression of a number of Myc target genes. We also observed that FOXO3a activation induced a switch in promoter occupancy from Myc to Mxi1 on the E-box containing promoter regions of two Myc target genes, APEX and FOXM1. siRNA-mediated transient silencing of Mxi1 or all Mad/Mxd proteins reduced exit from S phase in response to FOXO3a activation, and stable silencing of Mxi1 or Mad1 reduced the growth inhibitory effect of FOXO3a. We conclude that induction of Mad/Mxd proteins contributes to the inhibition of proliferation in response to FOXO3a activation. Our results provide evidence of direct regulation of Mxi1 by FOXO3a and imply an additional mechanism through which the PI3-kinase/Akt/FOXO pathway can modulate Myc function.

scholarly journals Highly multiplexed spatially resolved gene expression profiling of mouse organogenesis

2020 ◽  
Author(s):  
T. Lohoff ◽  
S. Ghazanfar ◽  
A. Missarova ◽  
N. Koulena ◽  
N. Pierson ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Resolution ◽  
Single Cell ◽  
Cell Fate ◽  
Target Genes ◽  
Single Cells ◽  
Spatial Context ◽  
Sequencing Data ◽  
Cell Fate Decisions ◽  
Spatially Resolved

AbstractTranscriptional and epigenetic profiling of single-cells has advanced our knowledge of the molecular bases of gastrulation and early organogenesis. However, current approaches rely on dissociating cells from tissues, thereby losing the crucial spatial context that is necessary for understanding cell and tissue interactions during development. Here, we apply an image-based single-cell transcriptomics method, seqFISH, to simultaneously and precisely detect mRNA molecules for 387 selected target genes in 8-12 somite stage mouse embryo tissue sections. By integrating spatial context and highly multiplexed transcriptional measurements with two single-cell transcriptome atlases we accurately characterize cell types across the embryo and demonstrate how spatially-resolved expression of genes not profiled by seqFISH can be imputed. We use this high-resolution spatial map to characterize fundamental steps in the patterning of the midbrain-hindbrain boundary and the developing gut tube. Our spatial atlas uncovers axes of resolution that are not apparent from single-cell RNA sequencing data – for example, in the gut tube we observe early dorsal-ventral separation of esophageal and tracheal progenitor populations. In sum, by computationally integrating high-resolution spatially-resolved gene expression maps with single-cell genomics data, we provide a powerful new approach for studying how and when cell fate decisions are made during early mammalian development.

Progesterone Receptors Promote Quiescence & Ovarian Cancer Cell Phenotypes via DREAM in p53-Mutant Fallopian Tube Models

2021 ◽  
Author(s):  
Laura J Mauro ◽  
Megan I Seibel ◽  
Caroline H Diep ◽  
Angela Spartz ◽  
Carlos Perez Kerkvliet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Ovarian Cancer ◽  
Fallopian Tube ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Progesterone Receptors ◽  
Invasive Disease ◽  
Clinical Samples ◽  
Oncogenic Signaling

Abstract Content The ability of ovarian steroids to modify ovarian cancer (OC) risk remains controversial. Progesterone is considered to be protective; recent studies indicate no effect or enhanced OC risk. Knowledge of progesterone receptor (PR) signaling during altered physiology that typifies OC development is limited. This study defines PR-driven oncogenic signaling mechanisms in p53-mutant human fallopian tube epithelia (hFTE), a precursor of the most aggressive OC subtype. Methods PR expression in clinical samples of serous tubal intraepithelial carcinoma (STIC) lesions and high grade serous OC (HGSC) tumors was analyzed. Novel PR-A and PR-B isoform-expressing hFTE models were characterized for gene expression and cell cycle progression, emboli formation, and invasion. PR regulation of the DREAM quiescence complex and DYRK1 kinases was established. Results STICs and HGSC express abundant activated phospho-PR. Progestin promoted reversible hFTE cell cycle arrest, spheroid formation and invasion. RNAseq/biochemical studies revealed potent ligand-independent/-dependent PR actions, progestin induced regulation of the DREAM quiescence complex and cell-cycle target genes through enhanced complex formation and chromatin recruitment. Disruption of DREAM/DYRK1s by pharmacological inhibition, HPV E6/E7 expression or DYRK1A/B depletion blocked progestin-induced cell arrest and attenuated PR-driven gene expression and associated OC phenotypes. Conclusion Activated PRs support quiescence and pro-survival/pro-dissemination cell behaviors that may contribute to early HGSC progression. Our data support an alternative perspective on the tenant that progesterone always confers protection against OC. STICs can reside undetected for decades prior to invasive disease; our studies reveal clinical opportunities to prevent the ultimate development of HGSC by targeting PRs, DREAM, and/or DYRKs.

scholarly journals sciCNV: High-throughput paired profiling of transcriptomes and DNA copy number variations at single cell resolution

2020 ◽  
Author(s):  
Ali Mahdipour-Shirayeh ◽  
Natalie Erdmann ◽  
Chungyee Leung-Hagesteijn ◽  
Rodger E. Tiedemann
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Copy Number ◽  
Target Genes ◽  
Single Cells ◽  
Copy Number Variations ◽  
Cellular Reprogramming ◽  
Cellular Effects ◽  
Normalization Methods ◽  
Cnv Detection

SUMMARYChromosome copy number variations (CNVs) are a near-universal feature of cancer however their effects on cellular function are incompletely understood. Single cell RNA sequencing (scRNA-seq) can reveal cellular gene expression however cannot directly link this to CNVs. Here we report new normalization methods (RTAM1 and −2) for scRNA-seq that improve gene expression alignment between cells, enhancing gene expression comparisons and the application of scRNA-seq to CNV detection. We also report sciCNV, a pipeline for inferring CNVs from RTAM-normalized data. Together, these tools provide dual profiling of transcriptomes and CNVs at single-cell resolution, enabling exploration of the effects of cancer CNVs on cellular programs. We apply these tools to multiple myeloma (MM) and examine the cellular effects of cancer CNVs +8q. Consistent with prior reports, MM cells with +8q22-24 upregulate MYC, MYC-target genes, mRNA processing and protein synthesis, verifying the approach. Overall, we provide new tools for scRNA-seq that enable matched profiling of the CNV landscape and transcriptome of single cells, facilitate deconstruction of the effects of cancer CNVs on cellular reprogramming within single samples.

scholarly journals The in vivo gene expression signature of oxidative stress

2008 ◽  
Vol 34 (1) ◽  
pp. 112-126 ◽  
Author(s):  
Eun-Soo Han ◽  
Florian L. Muller ◽  
Viviana I. Pérez ◽  
Wenbo Qi ◽  
Huiyun Liang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Oxidative Damage ◽  
Target Genes ◽  
Wild Type ◽  
Antioxidant Genes ◽  
Genetic Ablation ◽  
Expression Response ◽  
P53 Target Genes

How higher organisms respond to elevated oxidative stress in vivo is poorly understood. Therefore, we measured oxidative stress parameters and gene expression alterations (Affymetrix arrays) in the liver caused by elevated reactive oxygen species induced in vivo by diquat or by genetic ablation of the major antioxidant enzymes CuZn-superoxide dismutase ( Sod1) and glutathione peroxidase-1 ( Gpx1). Diquat (50 mg/kg) treatment resulted in a significant increase in oxidative damage within 3–6 h in wild-type mice without any lethality. In contrast, treatment of Sod1−/− or Gpx1−/− mice with a similar concentration of diquat resulted in a significant increase in oxidative damage within an hour of treatment and was lethal, i.e., these mice are extremely sensitive to the oxidative stress generated by diquat. The expression response to elevated oxidative stress in vivo does not involve an upregulation of classic antioxidant genes, although long-term oxidative stress in Sod1−/− mice leads to a significant upregulation of thiol antioxidants (e.g., Mt1, Srxn1, Gclc, Txnrd1), which appears to be mediated by the redox-sensitive transcription factor Nrf2. The main finding of our study is that the common response to elevated oxidative stress with diquat treatment in wild-type, Gpx1−/−, and Sod1−/− mice and in untreated Sod1−/− mice is an upregulation of p53 target genes ( p21, Gdf15, Plk3, Atf3, Trp53inp1, Ddit4, Gadd45a, Btg2, Ndrg1). A retrospective comparison with previous studies shows that induction of these p53 target genes is a conserved expression response to oxidative stress, in vivo and in vitro, in different species and different cells/organs.

scholarly journals Cell cycle progression inCaulobacterrequires a nucleoid-associated protein with high AT sequence recognition

2016 ◽  
Vol 113 (40) ◽  
pp. E5952-E5961 ◽  
Author(s):  
Dante P. Ricci ◽  
Michael D. Melfi ◽  
Keren Lasker ◽  
David L. Dill ◽  
Harley H. McAdams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Binding Sites ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Caulobacter Crescentus ◽  
Regulation Of Gene Expression ◽  
Cycle Progression ◽  
Swarmer Cell ◽  
Sequence Recognition

Faithful cell cycle progression in the dimorphic bacteriumCaulobacter crescentusrequires spatiotemporal regulation of gene expression and cell pole differentiation. We discovered an essential DNA-associated protein, GapR, that is required forCaulobactergrowth and asymmetric division. GapR interacts with adenine and thymine (AT)-rich chromosomal loci, associates with the promoter regions of cell cycle-regulated genes, and shares hundreds of recognition sites in common with known master regulators of cell cycle-dependent gene expression. GapR target loci are especially enriched in binding sites for the transcription factors GcrA and CtrA and overlap with nearly all of the binding sites for MucR1, a regulator that controls the establishment of swarmer cell fate. Despite constitutive synthesis, GapR accumulates preferentially in the swarmer compartment of the predivisional cell. Homologs of GapR, which are ubiquitous among the α-proteobacteria and are encoded on multiple bacteriophage genomes, also accumulate in the predivisional cell swarmer compartment when expressed inCaulobacter. TheEscherichia colinucleoid-associated protein H-NS, like GapR, selectively associates with AT-rich DNA, yet it does not localize preferentially to the swarmer compartment when expressed exogenously inCaulobacter, suggesting that recognition of AT-rich DNA is not sufficient for the asymmetric accumulation of GapR. Further, GapR does not silence the expression of H-NS target genes when expressed inE. coli, suggesting that GapR and H-NS have distinct functions. We propose thatCaulobacterhas co-opted a nucleoid-associated protein with high AT recognition to serve as a mediator of cell cycle progression.

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