Regulation of angiogenesis by ETS transcription factors

2009 ◽  
Vol 37 (6) ◽  
pp. 1248-1253 ◽  
Author(s):  
Anna M. Randi ◽  
Andrea Sperone ◽  
Nicola H. Dryden ◽  
Graeme M. Birdsey
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Gene Transcription ◽  
Target Genes ◽  
Ets Transcription Factors ◽  
Ets Family ◽  
Endothelial Gene Expression ◽  
Ets Factors

Transcription factors of the ETS family are important regulators of endothelial gene expression. Here, we review the evidence that ETS factors regulate angiogenesis and briefly discuss the target genes and pathways involved. Finally, we discuss novel evidence that shows how these transcription factors act in a combinatorial fashion with others, through composite sites that may be crucial in determining endothelial specificity in gene transcription.

scholarly journals Recent advances in the structural molecular biology of Ets transcription factors: interactions, interfaces and inhibition

2014 ◽  
Vol 42 (1) ◽  
pp. 130-138 ◽  
Author(s):  
Christopher D.O. Cooper ◽  
Joseph A. Newman ◽  
Opher Gileadi
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Protein Interaction ◽  
Eukaryotic Transcription ◽  
Ets Transcription Factors ◽  
Recent Advances ◽  
Ets Family ◽  
Structural Mechanisms ◽  
Ets Factors ◽  
Binding Mechanisms

The Ets family of eukaryotic transcription factors is based around the conserved Ets DNA-binding domain. Although their DNA-binding selectivity is biochemically and structurally well characterized, structures of homodimeric and ternary complexes point to Ets domains functioning as versatile protein-interaction modules. In the present paper, we review the progress made over the last decade to elucidate the structural mechanisms involved in modulation of DNA binding and protein partner selection during dimerization. We see that Ets domains, although conserved around a core architecture, have evolved to utilize a variety of interaction surfaces and binding mechanisms, reflecting Ets domains as dynamic interfaces for both DNA and protein interaction. Furthermore, we discuss recent advances in drug development for inhibition of Ets factors, and the roles structural biology can play in their future.

Analysis of the ETS Family Member Genes ERG, ETS2, ETS1 and FLI1 in Acute Myeloid Leukemia (AML) Patients with Normal Cytogenetics: Expression Levels and Impact On Clinical Outcome. A Study of the AMLSG.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1600-1600 ◽  
Author(s):  
Verena I. Gaidzik ◽  
Cailian Wang ◽  
Richard F. Schlenk ◽  
Lars Bullinger ◽  
Peter Paschka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Clinical Outcome ◽  
Treatment Protocols ◽  
Ets Transcription Factors ◽  
Free Survival ◽  
Expression Levels ◽  
Ets Family ◽  
Multivariable Analyses ◽  
Normal Cytogenetics

Abstract Abstract 1600 Poster Board I-626 Background The V-ets erythroblastosis virus E26 (ETS) oncogene family is one of the largest families of transcription factors. ETS transcription factors are characterized by two major functional domains, a transcription domain and an evolutionarily highly conserved DNA-binding domain, also known as ETS domain that mediates binding to purine-rich DNA sequences. Most ETS family proteins are nuclear targets for activation of the Ras-MAP kinase signalling pathway. Therefore, they play a significant role in regulating cellular functions such as cell growth, apoptosis, development and differentiation. ETS transcription factors have been implicated in leukemia by chromosomal rearrangement, and more commonly by gene amplification and/or overexpression. Moreover, overexpression of ERG was shown to be an adverse predictor for clinical outcome in AML with normal cytogenetics (CN). In our recent study on complex karyotype AML, array-CGH (comparative genomic hybridization) analysis identified small genomic amplifications affecting ERG/ETS2 in 21q22 and ETS1/FLI1 in 11q23 in about 10% of the cases. Correlation with global gene expression profiling showed that ERG and ETS2 as well as ETS1 and FLI1 were overexpressed in these cases. Aims: To evaluate expression levels of ERG, ETS2, ETS1 and FLI1 in a large cohort of younger (16 to 60 years of age) adult CN-AML patients (pts) and their impact on clinical outcome. Methods The expression of ERG, ETS2, ETS1 and FLI1 was determined by quantitative real-time reverse transcriptase polymerase chain reaction (qPCR) assay in 343 CN-AML pts who were entered on 3 AMLSG treatment protocols (AMLHD93, AML HD98-A, AMLSG 07-04). ERG, ETS2, ETS1, and FLI1 were dichotomized into two major groups according to their expression levels. The upper quartile was chosen as the cut point and the set of patients with gene expression above were defined as Q4 group. Univariable as well as multivariable regression models were used to evaluate the influence of ERG, ETS2, ETS1 and FLI1 on induction success, event-free, relapse-free and overall survival. Multivariable analyses were stratified for AMLSG treatment protocols. Results Partial correlation analysis revealed positive correlations of expression levels between ETS2 and ERG (ρ=0.45) being the strongest, followed by ERG and FLI1 (ρ=0.4), as well as ETS1 and FLI1 (ρ=0.31). Correlation of ERG, ETS2, ETS1 and FLI1 with white blood count (WBC) revealed a significant association between high gene expression (Q4) and elevated WBC (ERG, p=0.004; ETS2, p=0.002, FLI1 p<0.001), whereas high expression of ETS1 was associated with a significantly lower WBC (p<0.001). Univariable as well as multivariable analyses on induction success revealed high ETS2 as an unfavourable marker (OR, 0.29, p=0.01). In univariable analysis, there was a significantly inferior relapse-free survival (RFS) and overall survival (OS) for high ERG (p=.01; p=.06, respectively) and high ETS2 (p=.002; p=.03, respectively) that was even more pronounced when both ERG Q4 and ETS2 Q4 (ERG Q4 ∩ ETS2 Q4) (p<0.001; p=.001, respectively) were included as one variable and compared with the rest. In multivariable analysis for the endpoints event-free survival (EFS), RFS and OS, a significant effect was found for RFS for ERG Q4 ∩ ETS2 Q4 (p=.002); the only significant variables that consistently appeared in the model were NPM1mut, FLT3-ITDpos and WBC. In subgroup analysis for the genotypes CEBPAmut, NPM1mut/FLT3-ITDneg, and all others (NPM1mut/FLT3-ITDpos, NPM1wt/FLT3-ITDpos, NPM1wt/FLT3-ITDneg) according to the hierarchical model, ERG Q4 was associated with an inferior EFS (p=.04) and OS (p=.03) in the favorable CEBPAmut genotype and became even more significant for the variable ERG Q4 ∩ ETS2 Q4 (EFS, p=.007, RFS, p=.002; OS, p=.06, respectively). For the NPM1mut/FLT3-ITDneg subgroup, again ERG Q4 ∩ ETS2 Q4 was associated with an adverse RFS (p=.04), but not with OS (p=0.07). Conclusions In our study on a large cohort of homogenously treated CN-AML patients, ERG and ETS2 expression were highly correlated. Overexpression of both genes had a significant impact on clinical outcome of CN-AML patients. Moreover, adverse effects of high ERG and high ETS2 expression on prognosis were also shown for the genetic AML subgroups CEBPAmut and NPM1mut/FLT3-ITDneg. Disclosures No relevant conflicts of interest to declare.

scholarly journals A family of transcription factors that limit lifespan: ETS factors have conserved roles in longevity

2018 ◽  
Author(s):  
Adam J. Dobson ◽  
Richard Boulton-McDonald ◽  
Lara Houchou ◽  
Ziyu Ren ◽  
Mimoza Hoti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Transcriptional Networks ◽  
Regulation Of Transcription ◽  
Detailed Knowledge ◽  
Extended Lifespan ◽  
Ets Family ◽  
Ets Factors

ABSTRACTIncreasing average population age, and the accompanying burden of ill health, is one of the public health crises of our time. Understanding the basic biology of the ageing process may help ameliorate the pathologies that characterise old age. Ageing can be modulated, often through changes in gene expression where regulation of transcription plays a pivotal role. Activities of Forkhead transcription factors (TFs) are known to extend lifespan, but detailed knowledge of the broader transcriptional networks that promote longevity is lacking. This study focuses on the E twenty-six (ETS) family of TFs. This family of TFs is large, conserved across metazoa, and known to play roles in development and cancer, but the role of its members in ageing has not been studied extensively. InDrosophila, an ETS transcriptional repressor,Aop, and an ETS transcriptional activator,Pnt, are known to genetically interact withFoxoand activatingAopis sufficient to extend lifespan. Here, it is shown thatAopandFoxoeffect a related gene-expression programme. Additionally,Aopcan modulateFoxo’s transcriptional output to moderate or synergise withFoxoactivity depending on promoter context, bothin vitroandin vivo.In vivogenome-wide mRNA expression analysis in response toAop,PntorFoxoindicated, and further experiments confirmed, that combinatorial activities of the three TFs dictate metabolic status, and that direct reduction ofPntactivity is sufficient to promote longevity. The role of ETS factors in longevity was not limited toPntandAop. Knockdown ofEts21corEip74EFin distinct cell types also extended lifespan, revealing that lifespan is limited by transcription from the ETS binding site in multiple cellular contexts. Reducing the activity of theC. elegansETS TFLin-1also extended lifespan, a finding that corroborates established evidence of roles of this TF family in ageing. Altogether, these results reveal the ETS family of TFs as pervasive and evolutionarily conserved brokers of longevity.

scholarly journals FgHtf1 Regulates Global Gene Expression towards Aerial Mycelium and Conidiophore Formation in the Cereal Fungal Pathogen Fusarium graminearum

2020 ◽  
Vol 86 (9) ◽  
Author(s):  
Gaili Fan ◽  
Huawei Zheng ◽  
Kai Zhang ◽  
Veena Devi Ganeshan ◽  
Stephen Obol Opiyo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Gene Family ◽  
Fusarium Graminearum ◽  
Target Genes ◽  
Homeobox Gene ◽  
Global Gene Expression ◽  
Binding Motifs ◽  
Content Type ◽  
Aerial Growth

ABSTRACT The homeobox gene family of transcription factors (HTF) controls many developmental pathways and physiological processes in eukaryotes. We previously showed that a conserved HTF in the plant-pathogenic fungus Fusarium graminearum, Htf1 (FgHtf1), regulates conidium morphology in that organism. This study investigated the mechanism of FgHtf1-mediated regulation and identified putative FgHtf1 target genes by a chromatin immunoprecipitation assay combined with parallel DNA sequencing (ChIP-seq) and RNA sequencing. A total of 186 potential binding peaks, including 142 genes directly regulated by FgHtf1, were identified. Subsequent motif prediction analysis identified two DNA-binding motifs, TAAT and CTTGT. Among the FgHtf1 target genes were FgHTF1 itself and several important conidiation-related genes (e.g., FgCON7), the chitin synthase pathway genes, and the aurofusarin biosynthetic pathway genes. In addition, FgHtf1 may regulate the cAMP-protein kinase A (PKA)-Msn2/4 and Ca2+-calcineurin-Crz1 pathways. Taken together, these results suggest that, in addition to autoregulation, FgHtf1 also controls global gene expression and promotes a shift to aerial growth and conidiation in F. graminearum by activation of FgCON7 or other conidiation-related genes. IMPORTANCE The homeobox gene family of transcription factors is known to be involved in the development and conidiation of filamentous fungi. However, the regulatory mechanisms and downstream targets of homeobox genes remain unclear. FgHtf1 is a homeobox transcription factor that is required for phialide development and conidiogenesis in the plant pathogen F. graminearum. In this study, we identified FgHtf1-controlled target genes and binding motifs. We found that, besides autoregulation, FgHtf1 also controls global gene expression and promotes conidiation in F. graminearum by activation of genes necessary for aerial growth, FgCON7, and other conidiation-related genes.

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 The role of insulin-like growth factor 2 receptor-mediated homeobox gene expression in human placental apoptosis, and its implications in idiopathic fetal growth restriction

2019 ◽  
Vol 25 (9) ◽  
pp. 572-585 ◽  
Author(s):  
Lynda K Harris ◽  
Priyadarshini Pantham ◽  
Hannah E J Yong ◽  
Anita Pratt ◽  
Anthony J Borg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Growth Factor ◽  
Cell Growth ◽  
Cell Line ◽  
Gene Transcription ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Homeobox Gene ◽  
Trophoblast Cell

Abstract Fetal growth restriction (FGR) is caused by poor placental development and function early in gestation. It is well known that placentas from women with FGR exhibit reduced cell growth, elevated levels of apoptosis and perturbed expression of the growth factors, cytokines and the homeobox gene family of transcription factors. Previous studies have reported that insulin-like growth factor-2 (IGF2) interacts with its receptor-2 (IGF2R) to regulate villous trophoblast survival and apoptosis. In this study, we hypothesized that human placental IGF2R-mediated homeobox gene expression is altered in FGR and contributes to abnormal trophoblast function. This study was designed to determine the association between IGF2R, homeobox gene expression and cell survival in pregnancies affected by FGR. Third trimester placentas were collected from FGR-affected pregnancies (n = 29) and gestation matched with control pregnancies (n = 30). Functional analyses were then performed in vitro using term placental explants (n = 4) and BeWo trophoblast cells. mRNA expression was determined by real-time PCR, while protein expression was examined by immunoblotting and immunohistochemistry. siRNA transfection was used to silence IGF2R expression in placental explants and the BeWo cell-line. cDNA arrays were used to screen for downstream targets of IGF2R, specifically homeobox gene transcription factors and apoptosis-related genes. Functional effects of silencing IGF2R were then verified by β-hCG ELISA, caspase activity assays and a real-time electrical cell-impedance assay for differentiation, apoptosis and cell growth potential, respectively. IGF2R expression was significantly decreased in placentas from pregnancies complicated by idiopathic FGR (P < 0.05 versus control). siRNA-mediated IGF2R knockdown in term placental explants and the trophoblast cell line BeWo resulted in altered expression of homeobox gene transcription factors, including increased expression of distal-less homeobox gene 5 (DLX5), and decreased expression of H2.0-Like Homeobox 1 (HLX) (P < 0.05 versus control). Knockdown of IGF2R transcription increased the expression and activity of caspase-6 and caspase-8 in placental explants, decreased BeWo proliferation and increased BeWo differentiation (all P < 0.05 compared to respective controls). This is the first study linking IGF2R placental expression with changes in the expression of homeobox genes that control cellular signalling pathways responsible for increased trophoblast cell apoptosis, which is a characteristic feature of FGR.

scholarly journals Combinatorial Regulation of Endothelial Gene Expression by Ets and Forkhead Transcription Factors

Cell ◽  
2008 ◽  
Vol 135 (6) ◽  
pp. 1053-1064 ◽  
Author(s):  
Sarah De Val ◽  
Neil C. Chi ◽  
Stryder M. Meadows ◽  
Simon Minovitsky ◽  
Joshua P. Anderson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Combinatorial Regulation ◽  
Forkhead Transcription Factors ◽  
Endothelial Gene Expression

scholarly journals CHD8 Is an ATP-Dependent Chromatin Remodeling Factor That Regulates β-Catenin Target Genes

2008 ◽  
Vol 28 (12) ◽  
pp. 3894-3904 ◽  
Author(s):  
Brandi A. Thompson ◽  
Véronique Tremblay ◽  
Grace Lin ◽  
Daniel A. Bochar
Keyword(s):  
Gene Expression ◽  
Rna Interference ◽  
Chromatin Remodeling ◽  
Gene Transcription ◽  
Chromatin Structure ◽  
Target Genes ◽  
Promoter Regions ◽  
Hairpin Rna ◽  
Short Hairpin ◽  
Targeted Gene Expression

ABSTRACT ATP-dependent chromatin remodeling by the CHD family of proteins plays an important role in the regulation of gene transcription. Here we report that full-length CHD8 interacts directly with β-catenin and that CHD8 is also recruited specifically to the promoter regions of several β-catenin-responsive genes. Our results indicate that CHD8 negatively regulates β-catenin-targeted gene expression, since short hairpin RNA against CHD8 results in the activation of several β-catenin target genes. This regulation is also conserved through evolution; RNA interference against kismet, the apparent Drosophila ortholog of CHD8, results in a similar activation of β-catenin target genes. We also report the first demonstration of chromatin remodeling activity for a member of the CHD6-9 family of proteins, suggesting that CHD8 functions in transcription through the ATP-dependent modulation of chromatin structure.

Sign in / Sign up

Export Citation Format

Share Document