scholarly journals The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2690
Author(s):  
Mónica Fernández-Cortés ◽  
Eduardo Andrés-León ◽  
Francisco Javier Oliver
Keyword(s):  
Transcription Factors ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Target Genes ◽  
Parp Inhibitor ◽  
Vasculogenic Mimicry ◽  
Transcriptome Profiling ◽  
Key Species ◽  
Non Coding Rnas ◽  
The Impact

In highly metastatic tumors, vasculogenic mimicry (VM) involves the acquisition by tumor cells of endothelial-like traits. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently used against tumors displaying BRCA1/2-dependent deficient homologous recombination, and they may have antimetastatic activity. Long non-coding RNAs (lncRNAs) are emerging as key species-specific regulators of cellular and disease processes. To evaluate the impact of olaparib treatment in the context of non-coding RNA, we have analyzed the expression of lncRNA after performing unbiased whole-transcriptome profiling of human uveal melanoma cells cultured to form VM. RNAseq revealed that the non-coding transcriptomic landscape differed between olaparib-treated and non-treated cells: olaparib significantly modulated the expression of 20 lncRNAs, 11 lncRNAs being upregulated, and 9 downregulated. We subjected the data to different bioinformatics tools and analysis in public databases. We found that copy-number variation alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressor genes. Furthermore, the lncRNAs that were modulated by olaparib appeared to be regulated by common transcription factors: ETS1 had high-score binding sites in the promoters of all olaparib upregulated lncRNAs, while MZF1, RHOXF1 and NR2C2 had high-score binding sites in the promoters of all olaparib downregulated lncRNAs. Finally, we predicted that olaparib-modulated lncRNAs could further regulate several transcription factors and their subsequent target genes in melanoma, suggesting that olaparib may trigger a major shift in gene expression mediated by the regulation lncRNA. Globally, olaparib changed the lncRNA expression landscape during VM affecting angiogenesis-related genes.

Mechanisms of Transcriptional Regulation and Transformation by HOXA9

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-30-SCI-30
Author(s):  
Jay L. Hess ◽  
Cailin Collins ◽  
Joel Bronstein ◽  
Yuqing Sun ◽  
Surya Nagaraja
Keyword(s):  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
A Genome ◽  
The Impact

Abstract Abstract SCI-30 HOXA9 plays important roles in both development and hematopoiesis and is overexpressed in more than 50 percent of acute myeloid leukemias (AML). Nearly all cases of AML with mixed lineage leukemia (MLL) translocations show increased HOXA9 expression, as well as cases with mutation of the nucleophosmin gene NPM1, overexpression of CDX2, and fusions of NUP98. In most cases, upregulation of HOXA9 is accompanied by upregulation of its homeodomain-containing cofactor MEIS1, which directly interacts with HOXA9. While HOXA9 alone is sufficient for transformation of hematopoietic stem cells in culture, the addition of MEIS1 increases the transformation efficiency and results in rapidly fatal leukemias in transplanted animals. Despite the crucial role that HOXA9 plays in development, hematopoiesis, and leukemia, its transcriptional targets and mechanisms of action are poorly understood. We have used ChIP-seq to identify Hoxa9 and Meis1 binding sites on a genome-wide level in myeloblastic cells, profiled their associated epigenetic modifications, identified the target genes regulated by HOXA9 and identified HOXA9 interacting proteins. HOXA9 and MEIS1 cobind at hundreds of promoter distal, highly evolutionarily conserved sites showing high levels of histone H3K4 monomethylation and CBP/P300 binding. These include many proleukemogenic gene loci, such as Erg, Flt3, Myb, Lmo2, and Sox4. In addition, HOXA9 binding sites overlap a subset of enhancers previously implicated in myeloid differentiation and inflammation. HOXA9 binding at enhancers stabilizes association of MEIS1 and lineage-restricted transcription factors, including C/EBPα, PU.1, and STAT5A/B thereby promoting CBP/p300 recruitment, histone acetylation, and transcriptional activation. Current efforts are focused on using both biochemical and genetic approaches to assess the role of HOXA9 “enhanceosome” components C/EBPα, PU.1, and STAT5A/B in transcriptional regulation and leukemogenesis. Studies to date suggest that C/EBPα and PU.1 binding can occur in the absence of HOXA9/MEIS1, supporting a model in which these proteins act as pioneer transcription factors for establishment of poised, but not activated, HOXA9-regulated enhancers. Work is under way to assess the impact of high-level HOXA9 and MEIS1 on enhanceosome assembly and the role of recruitment of transcriptional coactivators involved in target gene up- or downregulation, including histone acetyltransferases and chromatin remodeling complexes. Collectively, our findings suggest that HOXA9-regulated enhancers are a fundamental mechanism of HOX-mediated transcription in normal development that is deregulated in leukemia. Disclosures: No relevant conflicts of interest to declare.

Systematic genetic analysis of transcription factors to map the fission yeast transcription-regulatory network

2013 ◽  
Vol 41 (6) ◽  
pp. 1696-1700 ◽  
Author(s):  
Gordon Chua
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Fission Yeast ◽  
Regulatory Networks ◽  
Target Genes ◽  
Transcriptome Profiling ◽  
Transcriptional Regulatory Networks ◽  
Transcriptional Regulatory ◽  
Transcription Factor Genes ◽  
Almost All

Mapping transcriptional-regulatory networks requires the identification of target genes, binding specificities and signalling pathways of transcription factors. However, the characterization of each transcription factor sufficiently for deciphering such networks remains laborious. The recent availability of overexpression and deletion strains for almost all of the transcription factor genes in the fission yeast Schizosaccharomyces pombe provides a valuable resource to better investigate transcription factors using systematic genetics. In the present paper, I review and discuss the utility of these strain collections combined with transcriptome profiling and genome-wide chromatin immunoprecipitation to identify the target genes of transcription factors.

scholarly journals Genome-wide effects of chromatin on vitamin D signaling

2020 ◽  
Vol 64 (4) ◽  
pp. R45-R56 ◽  
Author(s):  
Andrea Hanel ◽  
Henna-Riikka Malmberg ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Binding Sites ◽  
Target Genes ◽  
Chromatin Accessibility ◽  
Transcription Start Sites ◽  
Dihydroxyvitamin D ◽  
Genome Wide ◽  
Spatio Temporal ◽  
Vitamin D Signaling ◽  
The Impact

Molecular endocrinology of vitamin D is based on the activation of the transcription factor vitamin D receptor (VDR) by the vitamin D metabolite 1α,25-dihydroxyvitamin D3. This nuclear vitamin D-sensing process causes epigenome-wide effects, such as changes in chromatin accessibility as well as in the contact of VDR and its supporting pioneer factors with thousands of genomic binding sites, referred to as vitamin D response elements. VDR binding enhancer regions loop to transcription start sites of hundreds of vitamin D target genes resulting in changes of their expression. Thus, vitamin D signaling is based on epigenome- and transcriptome-wide shifts in VDR-expressing tissues. Monocytes are the most responsive cell type of the immune system and serve as a paradigm for uncovering the chromatin model of vitamin D signaling. In this review, an alternative approach for selecting vitamin D target genes is presented, which are most relevant for understanding the impact of vitamin D endocrinology on innate immunity. Different scenarios of the regulation of primary upregulated vitamin D target genes are presented, in which vitamin D-driven super-enhancers comprise a cluster of persistent (constant) and/or inducible (transient) VDR-binding sites. In conclusion, the spatio-temporal VDR binding in the context of chromatin is most critical for the regulation of vitamin D target genes.

Identification of transcription factors MYC and C/EBPβ mediated regulatory networks in heart failure based on GEO dataset

2020 ◽  
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Hua Cao
Keyword(s):  
Heart Failure ◽  
Transcription Factors ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Regulatory Networks ◽  
Target Genes ◽  
Transcriptional Profiling ◽  
Insulin Signaling Pathway ◽  
Failing Heart

Abstract Background: Heart failure is one of leading cause of death worldwide. However, the transcriptional profiling of heart failure is unclear. Moreover, the signaling pathways and transcription factors involving the heart failure development also are largely unknown. Using published Gene Expression Omnibus (GEO) datasets, in the present study, we aim to comprehensively analyze the differentially expressed genes in failing heart tissues, and identified the critical signaling pathways and transcription factors involving heart failure development. Methods: The transcriptional profiling of heart failure was identified from previously published gene expression datasets deposited in GSE5406, GSE16499 and GSE68316. The enriched signaling pathways and transcription factors were analyzed using DAVID website and gene set enrichment analysis (GSEA) assay. The transcriptional networks were created by Cytoscape. Results: Compared with the normal heart tissues, 90 genes were particularly differentially expressed in failing heart tissues, and those genes were associated with multiple metabolism signaling pathways and insulin signaling pathway. Metabolism and insulin signaling pathway were both inactivated in failing heart tissues. Transcription factors MYC and C/EBPβ were both negatively associated with the expression profiling of failing heart tissues in GSEA assay. Moreover, compared with normal heart tissues, MYC and C/EBPβ were down regulated in failing heart tissues. Furthermore, MYC and C/EBPβ mediated downstream target genes were also decreased in failing heart tissues. MYC and C/EBPβ were positively correlated with each other. At last, we constructed MYC and C/EBPβ mediated regulatory networks in failing heart tissues, and identified the MYC and C/EBPβ target genes which had been reported involving the heart failure developmental progress. Conclusions: Our results suggested that metabolism pathways and insulin signaling pathway, transcription factors MYC and C/EBPβ played critical roles in heart failure developmental progress.

scholarly journals Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets

2016 ◽  
Vol 113 (13) ◽  
pp. E1835-E1843 ◽  
Author(s):  
Mina Fazlollahi ◽  
Ivor Muroff ◽  
Eunjee Lee ◽  
Helen C. Causton ◽  
Harmen J. Bussemaker
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Nonsynonymous Mutation ◽  
Gene Regulatory ◽  
Genetic Modulators

Regulation of gene expression by transcription factors (TFs) is highly dependent on genetic background and interactions with cofactors. Identifying specific context factors is a major challenge that requires new approaches. Here we show that exploiting natural variation is a potent strategy for probing functional interactions within gene regulatory networks. We developed an algorithm to identify genetic polymorphisms that modulate the regulatory connectivity between specific transcription factors and their target genes in vivo. As a proof of principle, we mapped connectivity quantitative trait loci (cQTLs) using parallel genotype and gene expression data for segregants from a cross between two strains of the yeast Saccharomyces cerevisiae. We identified a nonsynonymous mutation in the DIG2 gene as a cQTL for the transcription factor Ste12p and confirmed this prediction empirically. We also identified three polymorphisms in TAF13 as putative modulators of regulation by Gcn4p. Our method has potential for revealing how genetic differences among individuals influence gene regulatory networks in any organism for which gene expression and genotype data are available along with information on binding preferences for transcription factors.

scholarly journals Stochastic resonances in a distributed genetic broadcasting system: the NF κ B/I κ B paradigm

2018 ◽  
Vol 15 (138) ◽  
pp. 20170809 ◽  
Author(s):  
Zhipeng Wang ◽  
Davit A. Potoyan ◽  
Peter G. Wolynes
Keyword(s):  
Gene Regulatory Networks ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Stochastic Dynamics ◽  
Extracellular Signals ◽  
Broadcasting System ◽  
Gene Regulatory ◽  
And Performance ◽  
The Impact ◽  
Kinetic Regulation

Gene regulatory networks must relay information from extracellular signals to downstream genes in an efficient, timely and coherent manner. Many complex functional tasks such as the immune response require system-wide broadcasting of information not to one but to many genes carrying out distinct functions whose dynamical binding and unbinding characteristics are widely distributed. In such broadcasting networks, the intended target sites are also often dwarfed in number by the even more numerous non-functional binding sites. Taking the genetic regulatory network of NF κ B as an exemplary system we explore the impact of having numerous distributed sites on the stochastic dynamics of oscillatory broadcasting genetic networks pointing out how resonances in binding cycles control the network's specificity and performance. We also show that active kinetic regulation of binding and unbinding through molecular stripping of DNA bound transcription factors can lead to a higher coherence of gene-co-expression and synchronous clearance.

scholarly journals The Proneural Proteins Atonal and Scute Regulate Neural Target Genes through Different E-Box Binding Sites

2004 ◽  
Vol 24 (21) ◽  
pp. 9517-9526 ◽  
Author(s):  
Lynn M. Powell ◽  
Petra I. zur Lage ◽  
David R. A. Prentice ◽  
Biruntha Senthinathan ◽  
Andrew P. Jarman
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Binding Sites ◽  
Tandem Repeats ◽  
Target Genes ◽  
Expression Patterns ◽  
Sense Organ ◽  
Ample Evidence ◽  
E Box ◽  
Bhlh Transcription Factors

ABSTRACT For a particular functional family of basic helix-loop-helix (bHLH) transcription factors, there is ample evidence that different factors regulate different target genes but little idea of how these different target genes are distinguished. We investigated the contribution of DNA binding site differences to the specificities of two functionally related proneural bHLH transcription factors required for the genesis of Drosophila sense organ precursors (Atonal and Scute). We show that the proneural target gene, Bearded, is regulated by both Scute and Atonal via distinct E-box consensus binding sites. By comparing with other Ato-dependent enhancer sequences, we define an Ato-specific binding consensus that differs from the previously defined Scute-specific E-box consensus, thereby defining distinct EAto and ESc sites. These E-box variants are crucial for function. First, tandem repeats of 20-bp sequences containing EAto and ESc sites are sufficient to confer Atonal- and Scute-specific expression patterns, respectively, on a reporter gene in vivo. Second, interchanging EAto and ESc sites within enhancers almost abolishes enhancer activity. While the latter finding shows that enhancer context is also important in defining how proneural proteins interact with these sites, it is clear that differential utilization of DNA binding sites underlies proneural protein specificity.

scholarly journals A novel k-mer set memory (KSM) motif representation improves regulatory variant prediction

2017 ◽  
Author(s):  
Yuchun Guo ◽  
Kevin Tian ◽  
Haoyang Zeng ◽  
Xiaoyun Guo ◽  
David Kenneth Gifford
Keyword(s):  
Binding Sites ◽  
Regulatory Networks ◽  
Motif Discovery ◽  
De Novo ◽  
Binding Motif ◽  
Large Set ◽  
Public Resource ◽  
Regulatory Variant ◽  
The Impact

ABSTRACTThe representation and discovery of transcription factor (TF) sequence binding specificities is critical for understanding gene regulatory networks and interpreting the impact of disease-associated non-coding genetic variants. We present a novel TF binding motif representation, the K-mer Set Memory (KSM), which consists of a set of aligned k-mers that are over-represented at TF binding sites, and a new method called KMAC for de novo discovery of KSMs. We find that KSMs more accurately predict in vivo binding sites than position weight matrix models (PWMs) and other more complex motif models across a large set of ChIP-seq experiments. KMAC also identifies correct motifs in more experiments than four state-of-the-art motif discovery methods. In addition, KSM derived features outperform both PWM and deep learning model derived sequence features in predicting differential regulatory activities of expression quantitative trait loci (eQTL) alleles. Finally, we have applied KMAC to 1488 ENCODE TF ChIP-seq datasets and created a public resource of KSM and PWM motifs. We expect that the KSM representation and KMAC method will be valuable in characterizing TF binding specificities and in interpreting the effects of non-coding genetic variations.

scholarly journals Transcriptomic analysis at organ and time scale reveals gene regulatory networks controlling the sulfate starvation response of Solanum lycopersicum.

2020 ◽  
Author(s):  
Javier Canales ◽  
Felipe Uribe ◽  
Carlos Henríquez-Valencia ◽  
Carlos Lovazzano ◽  
Joaquín Medina ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Essential Element ◽  
Transcript Level ◽  
Central Component ◽  
Transcriptomic Response ◽  
Starvation Response ◽  
Expression Of Genes ◽  
The Impact

Abstract Background: Sulfur is a major component of biological molecules and thus an essential element for plants. Deficiency of sulfate, the main source of sulfur in soils, negatively influences plant growth and crop yield. The effect of sulfate deficiency on plants has been well characterized at the physiological, transcriptomic and metabolomic levels in Arabidopsis thaliana and a limited number of crop plants. However, we still lack a thorough understanding of the molecular mechanisms and regulatory networks underlying sulfate deficiency in most plants. In this work we analyzed the impact of sulfate starvation on the transcriptome of tomato plants to identify regulatory networks and key transcriptional regulators at a temporal and organ scale. Results: Sulfate starvation reduces the growth of roots and leaves which is accompanied by major changes in the organ transcriptome, with the response being temporally earlier in roots than leaves. Comparative analysis showed that a major part of the Arabidopsis and tomato transcriptomic response to sulfate starvation is conserved between these plants and allowed for the identification of processes specifically regulated in tomato at the transcript level, including the control of internal phosphate levels. Integrative gene network analysis uncovered key transcription factors controlling the temporal expression of genes involved in sulfate assimilation, as well as cell cycle, cell division and photosynthesis during sulfate starvation in tomato roots and leaves. Interestingly, one of these transcription factors presents a high identity with SULFUR LIMITATION1, a central component of the sulfate starvation response in Arabidopsis. Conclusions: Together, our results provide the first comprehensive catalog of sulfate-responsive genes in tomato, as well as novel regulatory targets for future functional analyses in tomato and other crops.

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