scholarly journals Complex networks of miRNA-transcription factors mediate gene dosage compensation in aneuploid cancer

2020 ◽  
Author(s):  
ManSai Acón ◽  
Guillermo Oviedo ◽  
Edwin Baéz ◽  
Gloriana Vásquez-Vargas ◽  
José Guevara-Coto ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Complex Networks ◽  
Dosage Compensation ◽  
Computational Models ◽  
Therapeutic Potential ◽  
Gene Dosage ◽  
Cancer Cell Line ◽  
Transcriptional Level ◽  
Negative Effects ◽  
Copy Numbers

AbstractCancer complexity is consequence of enormous genomic instability leading to aneuploidy, a hallmark of most cancers. We hypothesize that dosage compensation of critical genes could arise from systems-level properties of complex networks of microRNAs (miRNA) and transcription factors (TF) as a way for cancer cells to withstand the negative effects of aneuploidy. We studied gene dosage compensation at the transcriptional level on data of the NCI-60 cancer cell line panel with the aid of computational models to identify candidate genes with low tolerance to variation in gene expression despite high variation in copy numbers. We identified a network of TF and miRNAs validated interactions with those genes to construct a mathematical model where the property of dosage compensation emerged for MYC and STAT3. Compensation was mediated by feedback and feed-forward motifs with 4 miRNAs and was dependent on the kinetic parameters of these TF-miRNA interactions, indicating that network analysis was not enough to identify this emergent property. The inhibition of miRNAs compensating MYC suggest a therapeutic potential of targeting gene dosage compensation against aneuploid cancer.

scholarly journals MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer

2021 ◽  
Author(s):  
ManSai Acón ◽  
Carsten Geiß ◽  
Jorge Torres-Calvo ◽  
Guillermo Oviedo ◽  
Jorge L Arias-Arias ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Dosage Compensation ◽  
Patient Survival ◽  
Gene Dosage ◽  
Negative Effects ◽  
Over Expression ◽  
Factor Interactions ◽  
Computational Platform ◽  
Omic Data

AbstractCancer complexity is consequence of genomic instability leading to aneuploidy. We hypothesize that dosage compensation of critical genes arise from systems-level properties for cancer cells to withstand the negative effects of aneuploidy. We developed a computational platform to identify a network of miRNAs and transcription factors interacting with candidate dosage-compensated genes using NCI-60 multi-omic data. We next constructed a mathematical model where the property of dosage compensation emerged for MYC and STAT3 and was dependent on the kinetic parameters of their feedback and feed-forward interactions with four miRNAs. We developed a genetic tug-of-war approach by overexpressing an exogenous MYC sequence to experimentally validate MYC dosage compensation circuits as demonstrated by the over-expression of the three microRNAs involved and the respective down-regulation of endogenous MYC. In addition, MYC overexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in MYC-amplified colon cancer cells. The study of TCGA breast cancer patient data indicated that MYC dosage compensation could lead to lower patient survival, highlighting the potential of targeting gene dosage compensation to prevent aneuploid cancer progression.(BioNetUCR, available here: https://cloud.prislab.org/s/gt2W2jfZQx3E3Jm).

scholarly journals A correlation between Long noncoding RNA and unpaired DNA silencing in Drosophila

2016 ◽  
Author(s):  
Manika Pal-Bhadra ◽  
Indira Bag ◽  
Sreerangam N.C. L.V Pushpavalli ◽  
Avadhesha Surolia ◽  
Utpal Bhadra
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Gene Dosage ◽  
Genetic Material ◽  
Transcriptional Silencing ◽  
Transcriptional Level ◽  
Loss Of Function ◽  
Gene Dosage Effect ◽  
Copy Numbers ◽  
Dna Silencing

SUMMARYHybrid transgenes are often recognized as foreign genetic material by cell surveillance mechanisms and are repressed in expression inversely to their copy numbers. Here, we compare the expression of multiple Adh-promoter-white reporter (Adh-w) inserts in paired and unpaired configurations in Drosophila somatic cells. The unpaired copies exhibit a clear repression at the transcriptional level relative to paired gene dosage effect, which is dependent upon long noncoding RNA, Polycomb and piwi. Deficiency mapping using Adh-w constructs showed that a minimal sequence of 532 bp of the Adh promoter is required for unpaired DNA silencing. Long noncoding RNA detected from this region of the Adh promoter is abundant in the unpaired condition. It serves as a docking site for at least two proteins POLYCOMB and Piwi that are essential for active transcriptional silencing. The lesser abundance of noncoding RNAs in the paired configuration only allows PC binding. An active RNA-Protein complex binds to unpaired copies. The loss-of-function piwi mutation relieves transcriptional silencing even in association with POLYCOMB. It suggests that functional RNA-Piwi complex might create a silencing driven chromatin configuration by accumulating histone modifying enzymes at the Adh-w promoter target. This distinct transcriptional silencing that is stronger for unpaired DNA represents a novel mechanism to repress new transposon and foreign DNA insertions for protection of genome integrity.

scholarly journals The Regulatory Mechanism of Water Activities on Aflatoxins Biosynthesis and Conidia Development, and Transcription Factor AtfB Is Involved in This Regulation

Toxins ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 431
Author(s):  
Longxue Ma ◽  
Xu Li ◽  
Xiaoyun Ma ◽  
Qiang Yu ◽  
Xiaohua Yu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Environmental Factors ◽  
Health Risks ◽  
Sexual Development ◽  
Regulatory Mechanism ◽  
Food Storage ◽  
Economic Losses ◽  
Transcriptional Level ◽  
Conidia Production

Peanuts are frequently infected by Aspergillus strains and then contaminated by aflatoxins (AF), which brings out economic losses and health risks. AF production is affected by diverse environmental factors, especially water activity (aw). In this study, A. flavus was inoculated into peanuts with different aw (0.90, 0.95, and 0.99). Both AFB1 yield and conidia production showed the highest level in aw 0.90 treatment. Transcriptional level analyses indicated that AF biosynthesis genes, especially the middle- and later-stage genes, were significantly up-regulated in aw 0.90 than aw 0.95 and 0.99. AtfB could be the pivotal regulator response to aw variations, and could further regulate downstream genes, especially AF biosynthesis genes. The expressions of conidia genes and relevant regulators were also more up-regulated at aw 0.90 than aw 0.95 and 0.99, suggesting that the relative lower aw could increase A. flavus conidia development. Furthermore, transcription factors involved in sexual development and nitrogen metabolism were also modulated by different aw. This research partly clarified the regulatory mechanism of aw on AF biosynthesis and A. flavus development and it would supply some advice for AF prevention in food storage.

Gene dosage compensation in metafemales (3X; 2A) of Drosophila

Nature ◽  
1974 ◽  
Vol 248 (5449) ◽  
pp. 564-567 ◽  
Author(s):  
John C. Lucchesi ◽  
John M. Rawls ◽  
Gustavo Maroni
Keyword(s):  
Dosage Compensation ◽  
Gene Dosage

X chromosome gene dosage compensation in female mammals

1993 ◽  
Vol 4 (2) ◽  
pp. 129-139 ◽  
Author(s):  
Giuseppe Borsani ◽  
Andrea Ballabio
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Gene Dosage ◽  
Chromosome Gene

scholarly journals Evolution of dosage compensation does not depend on genomic background

2020 ◽  
Author(s):  
Michail Rovatsos ◽  
Lukáš Kratochvíl
Keyword(s):  
Dosage Compensation ◽  
Sex Chromosomes ◽  
Sex Chromosome ◽  
Genomic Region ◽  
Gene Copy ◽  
Gene Dose ◽  
Copy Numbers ◽  
Compensation Mechanisms ◽  
Gene Copy Numbers ◽  
Softshell Turtles

AbstractOrganisms evolved various mechanisms to cope with the differences in the gene copy numbers between sexes caused by degeneration of Y and W sex chromosomes. Complete dosage compensation or at least expression balance between sexes was reported predominantly in XX/XY, but rarely in ZZ/ZW systems. However, this often-reported pattern is based on comparisons of lineages where sex chromosomes evolved from non-homologous genomic regions, potentially differing in sensitivity to differences in gene copy numbers. Here we document that two reptilian lineages (XX/XY iguanas and ZZ/ZW softshell turtles), which independently co-opted the same ancestral genomic region for the function of sex chromosomes, evolved different gene dose regulatory mechanisms. The independent co-option of the same genomic region for the role of sex chromosome as in the iguanas and the softshell turtles offers a great opportunity for testing evolutionary scenarios on the sex chromosome evolution under the explicit control for the genomic background and for gene identity. We showed that the parallel loss of functional genes from the Y chromosome of the green anole and the W chromosome of the Florida softshell turtle led to different dosage compensation mechanisms. Our approach controlling for genetic background thus does not support that the variability in the regulation of the gene dose differences is a consequence of ancestral autosomal gene content.

scholarly journals On the Mode of Gene-Dosage Compensation in Drosophila

Genetics ◽  
1997 ◽  
Vol 145 (3) ◽  
pp. 729-736
Author(s):  
Irina Arkhipova ◽  
Jingjing Li ◽  
Matthew Meselson
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Gene Dosage ◽  
Gene Activity ◽  
Gene Copy ◽  
Drosophila Pseudoobscura ◽  
A Site ◽  
Reduced Activity ◽  
Per Gene

A procedure is described for determining the mode and magnitude of gene-dosage compensation of transformed genes. It involves measurement of the ratio of the activity of a gene inserted at X-linked sites to the activity of the same gene inserted at autosomal sites. Applying the procedure to the Drosophila pseudoobscura Hsp82 gene inserted at ectopic sites in D. melanogaster and taking gene activity as proportional to the amount of transcript per gene copy, we conclude that (1) in both adults and larvae the gene is not compensated at autosomal sites or at a site in β-heterochromatin at the base of the X chromosome and is fully compensated at euchromatic X-chromosomal sites; (2) inappropriate normalization is responsible for a claim that the gene is compensated at autosomal sites; and (3) the observed compensation operates mainly or entirely by heightened activity of X-linked genes in males, rather than by reduced activity in females.

scholarly journals Concatemeric Broccoli reduces mRNA stability, aggregates and induces p-body formation

2020 ◽  
Author(s):  
Marco R. Rink ◽  
Marisa A.P. Baptista ◽  
Thomas Hennig ◽  
Adam W. Whisnant ◽  
Natalia Wolf ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Substrate Binding ◽  
Rna Stability ◽  
Time Lapse ◽  
Negative Effects ◽  
Imaging Protocol ◽  
P Bodies ◽  
Copy Numbers ◽  
Substrate Binding Sites ◽  
Time Lapse Imaging

AbstractFluorogenic aptamers are an alternative to established methodology for real-time imaging of RNA transport and dynamics. We developed Broccoli-aptamer concatemers ranging from 4 to 128 substrate-binding site repeats and characterized their behavior fused to an mCherry-coding mRNA in transient transfection, stable expression, and in recombinant cytomegalovirus infection. Concatemerization of substrate-binding sites increased Broccoli fluorescence up to a concatemer length of 16 copies, upon which fluorescence did not increase and mCherry signals declined. This was due to the combined effects of RNA aptamer aggregation, a nuclear export defect and reduced RNA stability. Unfortunately, both cellular and cytomegalovirus genomes were unable to maintain and express high Broccoli concatemer copy numbers, possibly due to recombination events. Overexpression of Broccoli-tagged mRNA led to the formation of p-bodies. However, Broccoli RNAs did not localize to these sites. Interestingly, negative effects of Broccoli concatemers could be partially rescued by introducing linker sequences in between Broccoli repeats warranting further studies. Finally, we show that even though substrate-bound Broccoli is easily photobleached, it can still be utilized in live-cell imaging by adapting a time-lapse imaging protocol.

scholarly journals THE GENETIC BASIS OF DOSAGE COMPENSATION OF ALCOHOL DEHYDROGENASE-1 IN MAIZE

Genetics ◽  
1981 ◽  
Vol 97 (3-4) ◽  
pp. 625-637 ◽  
Author(s):  
James A Birchler
Keyword(s):  
Alcohol Dehydrogenase ◽  
Structural Gene ◽  
Dosage Compensation ◽  
Genetic Basis ◽  
Gene Dosage ◽  
Dosage Effect ◽  
Gene Dosage Effect ◽  
Negative Effect ◽  
Higher Eukaryotes ◽  
Alcohol Dehydrogenase 1

ABSTRACT The levels of alcohol dehydrogenase (ADH) do not exhibit a structural gene-dosage effect in a one to four dosage series of the long arm of chromosome one (1L) (BIRCHLER19 79). This phenomenon, termed dosage compensation, has been studied in more detail. Experiments are described in which individuals aneuploid for shorter segments were examined for the level of ADH in order to characterize the genetic nature of the compensation. The relative ADH expression in segmental trisomics and tetrasomics of region IL 0.72–0.90, which includes the Adh locus, approaches the level expected from a strict gene dosage effect. Region IL 0.20–0.72 produces a negative effect upon ADH in a similar manner to that observed with other enzyme levels when IL as a whole is varied (BIRCHLEF1I9 79). These and other comparisons have led to the concept that the compensation of ADH results from the cancellation of the structural gene effect by the negative aneuploid effect. The example of ADH is discussed as a model for certain other cases of dosage compensation in higher eukaryotes.

scholarly journals miR-204 Shifts the Epithelial to Mesenchymal Transition in Concert with the Transcription Factors RUNX2, ETS1, and cMYB in Prostate Cancer Cell Line Model

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Krassimira Todorova ◽  
Diana Zasheva ◽  
Kristiyan Kanev ◽  
Soren Hayrabedyan
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Cancer Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Prostate Cancer Cell ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Mesenchymal Transition ◽  
Cell Line Model ◽  
E Cadherin

Epithelial to mesenchymal transition is an essential step in advanced cancer development. Many master transcription factors shift their expression to drive this process, while noncoding RNAs families like miR-200 are found to restrict it. In this study we investigated how the tumor suppressor miR-204 and several transcription factors modulate main markers of mesenchymal transformation like E- and N-cadherin, SLUG, VEGF, and SOX-9 in prostate cancer cell line model (LNCaP, PC3, VCaP, and NCI-H660). We found that SLUG, E-cadherin, and N-cadherin are differentially modulated by miR-204, using miR-204 specific mimics and inhibitors and siRNA gene silencing (RUNX2, ETS-1, and cMYB). The genome perturbation associated TMPRSS2-ERG fusion coincided with shift from tumor-suppressor to tumor-promoting activity of this miRNA. The ability of miR-204 to suppress cancer cell viability and migration was lost in the fusion harboring cell lines. We found differential E-cadherin splicing corroborating to miR-204 modulatory effects. RUNX2, ETS1, and cMYB are involved in the regulation of E-cadherin, N-cadherin, and VEGFA expression. RUNX2 knockdown results in SOX9 downregulation, while ETS1 and cMYB silencing result in SOX9 upregulation in VCaP cells. Their expression was found to be also methylation dependent. Our study provides means for understanding cancer heterogeneity in regard to adapted therapeutic approaches development.

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