scholarly journals Reverse Engineering of Ewing Sarcoma Regulatory Network Uncovers PAX7 and RUNX3 as Master Regulators Associated with Good Prognosis

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1860
Author(s):  
Marcel da Câmara Ribeiro-Dantas ◽  
Danilo Oliveira Imparato ◽  
Matheus Gibeke Siqueira Dalmolin ◽  
Caroline Brunetto de Farias ◽  
André Tesainer Brunetto ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Prognostic Factors ◽  
Ewing Sarcoma ◽  
Regulatory Network ◽  
Chromosomal Translocation ◽  
Good Prognosis ◽  
Regulatory Mechanisms ◽  
Es Cell ◽  
Master Regulators ◽  
Transcriptional Alterations

Ewing Sarcoma (ES) is a rare malignant tumor occurring most frequently in adolescents and young adults. The ES hallmark is a chromosomal translocation between the chromosomes 11 and 22 that results in an aberrant transcription factor (TF) through the fusion of genes from the FET and ETS families, commonly EWSR1 and FLI1. The regulatory mechanisms behind the ES transcriptional alterations remain poorly understood. Here, we reconstruct the ES regulatory network using public available transcriptional data. Seven TFs were identified as potential MRs and clustered into two groups: one composed by PAX7 and RUNX3, and another composed by ARNT2, CREB3L1, GLI3, MEF2C, and PBX3. The MRs within each cluster act as reciprocal agonists regarding the regulation of shared genes, regulon activity, and implications in clinical outcome, while the clusters counteract each other. The regulons of all the seven MRs were differentially methylated. PAX7 and RUNX3 regulon activity were associated with good prognosis while ARNT2, CREB3L1, GLI3, and PBX3 were associated with bad prognosis. PAX7 and RUNX3 appear as highly expressed in ES biopsies and ES cell lines. This work contributes to the understanding of the ES regulome, identifying candidate MRs, analyzing their methilome and pointing to potential prognostic factors.

scholarly journals Reverse Engineering of the Pediatric Sepsis Regulatory Network and Identification of Master Regulators

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1297
Author(s):  
Raffael Azevedo de Carvalho Oliveira ◽  
Danilo Oliveira Imparato ◽  
Vítor Gabriel Saldanha Fernandes ◽  
João Vitor Ferreira Cavalcante ◽  
Ricardo D’Oliveira Albanus ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retrospective Study ◽  
Regulatory Network ◽  
Regulatory Mechanisms ◽  
Master Regulators ◽  
Genetic Biomarkers ◽  
Promising Strategy ◽  
The World ◽  
Pediatric Sepsis ◽  
Increased Activity

Sepsis remains a leading cause of death in ICUs all over the world, with pediatric sepsis accounting for a high percentage of mortality in pediatric ICUs. Its complexity makes it difficult to establish a consensus on genetic biomarkers and therapeutic targets. A promising strategy is to investigate the regulatory mechanisms involved in sepsis progression, but there are few studies regarding gene regulation in sepsis. This work aimed to reconstruct the sepsis regulatory network and identify transcription factors (TFs) driving transcriptional states, which we refer to here as master regulators. We used public gene expression datasets to infer the co-expression network associated with sepsis in a retrospective study. We identified a set of 15 TFs as potential master regulators of pediatric sepsis, which were divided into two main clusters. The first cluster corresponded to TFs with decreased activity in pediatric sepsis, and GATA3 and RORA, as well as other TFs previously implicated in the context of inflammatory response. The second cluster corresponded to TFs with increased activity in pediatric sepsis and was composed of TRIM25, RFX2, and MEF2A, genes not previously described as acting in a coordinated way in pediatric sepsis. Altogether, these results show how a subset of master regulators TF can drive pathological transcriptional states, with implications for sepsis biology and treatment.

scholarly journals Recording of DNA binding events during gut commensalism reveals the action of a repurposed Candida albicans regulatory network

2020 ◽  
Author(s):  
Jessica N. Witchley ◽  
Cedric A. Brimacombe ◽  
Nina V. Abon ◽  
Suzanne M. Noble
Keyword(s):  
Transcription Factor ◽  
Candida Albicans ◽  
Dna Binding ◽  
Regulatory Network ◽  
Opportunistic Pathogen ◽  
Human Gut ◽  
Epigenetic Switch ◽  
Master Regulators ◽  
Gut Colonization

ABSTRACTCandida albicans is a central fungal component of the human gut microbiota and an opportunistic pathogen. Two C. albicans transcription factors, Wor1 and Efg1, control its ability to colonize the mammalian gut. They are also master regulators of an epigenetic switch required for mating. Here, we show that six additional mating regulators influence gut commensalism. Using an adapted Calling Card-Seq protocol to record Candida transcription factor DNA binding events in the host, we validated these relationships during murine gut colonization. Finally, by comparing the in-host transcriptomes of regulatory mutants with enhanced vs. diminished commensal fitness, we identified a set of candidate commensalism effectors. These include Cht2, a GPI-linked chitinase whose gene is bound by Wor1, Czf1, and Efg1 in vivo and that we show to promote commensalism. We conclude that the network required for a C. albicans sexual switch is biochemically active in the host digestive tract, where it is repurposed to direct commensalism.

A Congenital Anemia Reveals Distinct Targeting Mechanisms for Master Transcription Factor GATA1

Blood ◽  
2022 ◽  
Author(s):  
Leif Ludwig ◽  
Caleb A Lareau ◽  
Erik L. Bao ◽  
Nan Liu ◽  
Taiju Utsugisawa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cellular Differentiation ◽  
Transcriptional Activity ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Mechanisms ◽  
Red Cell ◽  
Missense Mutations ◽  
Master Regulators ◽  
Intrinsically Disordered

Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation.

Construction of transcription factor mutual regulatory network based on a new database

2014 ◽  
Author(s):  
Zhenping Yang ◽  
Wei Wang ◽  
Yang Yang ◽  
Hongfei Chen ◽  
Jinke Wang
Keyword(s):  
Transcription Factor ◽  
Regulatory Network

scholarly journals Multi-omic regulatory networks capture downstream effects of kinase inhibition in Mycobacterium tuberculosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Albert T. Young ◽  
Xavier Carette ◽  
Michaela Helmel ◽  
Hanno Steen ◽  
Robert N. Husson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mycobacterium Tuberculosis ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Protein Interaction Data ◽  
Kinase Inhibition ◽  
Protein Protein Interaction ◽  
Downstream Effects ◽  
Regulate Cell Growth ◽  
Regulatory Effects

AbstractThe ability of Mycobacterium tuberculosis (Mtb) to adapt to diverse stresses in its host environment is crucial for pathogenesis. Two essential Mtb serine/threonine protein kinases, PknA and PknB, regulate cell growth in response to environmental stimuli, but little is known about their downstream effects. By combining RNA-Seq data, following treatment with either an inhibitor of both PknA and PknB or an inactive control, with publicly available ChIP-Seq and protein–protein interaction data for transcription factors, we show that the Mtb transcription factor (TF) regulatory network propagates the effects of kinase inhibition and leads to widespread changes in regulatory programs involved in cell wall integrity, stress response, and energy production, among others. We also observe that changes in TF regulatory activity correlate with kinase-specific phosphorylation of those TFs. In addition to characterizing the downstream regulatory effects of PknA/PknB inhibition, this demonstrates the need for regulatory network approaches that can incorporate signal-driven transcription factor modifications.

scholarly journals Regulatory Network Analysis in Estradiol-Treated Human Endothelial Cells

2021 ◽  
Vol 22 (15) ◽  
pp. 8193
Author(s):  
Daniel Pérez-Cremades ◽  
Ana B. Paes ◽  
Xavier Vidal-Gómez ◽  
Ana Mompeón ◽  
Carlos Hermenegildo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Mirna Target ◽  
Target Genes ◽  
Functional Characterization ◽  
Human Endothelial Cells ◽  
Mrna Targets ◽  
Canonical Pathways

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a comprehensive regulatory network (miRNA-transcription factor-downstream genes) that controls the transcriptomic changes observed in endothelial cells exposed to estradiol. Methods: miRNA/mRNA interactions were assembled using our previous microarray data of human umbilical vein endothelial cells (HUVEC) treated with 17β-estradiol (E2) (1 nmol/L, 24 h). miRNA–mRNA pairings and their associated canonical pathways were determined using Ingenuity Pathway Analysis software. Transcription factors were identified among the miRNA-regulated genes. Transcription factor downstream target genes were predicted by consensus transcription factor binding sites in the promoter region of E2-regulated genes by using JASPAR and TRANSFAC tools in Enrichr software. Results: miRNA–target pairings were filtered by using differentially expressed miRNAs and mRNAs characterized by a regulatory relationship according to miRNA target prediction databases. The analysis identified 588 miRNA–target interactions between 102 miRNAs and 588 targets. Specifically, 63 upregulated miRNAs interacted with 295 downregulated targets, while 39 downregulated miRNAs were paired with 293 upregulated mRNA targets. Functional characterization of miRNA/mRNA association analysis highlighted hypoxia signaling, integrin, ephrin receptor signaling and regulation of actin-based motility by Rho among the canonical pathways regulated by E2 in HUVEC. Transcription factors and downstream genes analysis revealed eight networks, including those mediated by JUN and REPIN1, which are associated with cadherin binding and cell adhesion molecule binding pathways. Conclusion: This study identifies regulatory networks obtained by integrative microarray analysis and provides additional insights into the way estradiol could regulate endothelial function in human endothelial cells.

Treatment results of the Ewing sarcoma of bone and prognostic factors

2009 ◽  
Vol 54 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Neriman Sarı ◽  
Giray Toğral ◽  
M. Faik Çetindağ ◽  
B. Şafak Güngör ◽  
İnci Ergürhan İlhan
Keyword(s):  
Prognostic Factors ◽  
Ewing Sarcoma ◽  
Treatment Results

scholarly journals Screening Driving Transcription Factors in the Processing of Gastric Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Guangzhong Xu ◽  
Kai Li ◽  
Nengwei Zhang ◽  
Bin Zhu ◽  
Guosheng Feng
Keyword(s):  
Gastric Cancer ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Expression Profiles ◽  
Functional Enrichment ◽  
Regulatory Mechanisms ◽  
Integrated Analysis ◽  
Transcriptional Regulatory

Background. Construction of the transcriptional regulatory network can provide additional clues on the regulatory mechanisms and therapeutic applications in gastric cancer.Methods. Gene expression profiles of gastric cancer were downloaded from GEO database for integrated analysis. All of DEGs were analyzed by GO enrichment and KEGG pathway enrichment. Transcription factors were further identified and then a global transcriptional regulatory network was constructed.Results. By integrated analysis of the six eligible datasets (340 cases and 43 controls), a bunch of 2327 DEGs were identified, including 2100 upregulated and 227 downregulated DEGs. Functional enrichment analysis of DEGs showed that digestion was a significantly enriched GO term for biological process. Moreover, there were two important enriched KEGG pathways: cell cycle and homologous recombination. Furthermore, a total of 70 differentially expressed TFs were identified and the transcriptional regulatory network was constructed, which consisted of 566 TF-target interactions. The top ten TFs regulating most downstream target genes were BRCA1, ARID3A, EHF, SOX10, ZNF263, FOXL1, FEV, GATA3, FOXC1, and FOXD1. Most of them were involved in the carcinogenesis of gastric cancer.Conclusion. The transcriptional regulatory network can help researchers to further clarify the underlying regulatory mechanisms of gastric cancer tumorigenesis.

scholarly journals Rational design of a stapled JAZ9 peptide inhibiting protein–protein interaction of a plant transcription factor

2021 ◽  
Author(s):  
Kaho Suzuki ◽  
Yousuke Takaoka ◽  
Minoru Ueda
Keyword(s):  
Arabidopsis Thaliana ◽  
Transcription Factor ◽  
Protein Interaction ◽  
Rational Design ◽  
Master Regulators ◽  
Jasmonate Signaling ◽  
Protein Protein Interaction ◽  
Inhibiting Protein

A rationally designed stapled JAZ peptide selectively inhibited MYCs, master-regulators of the jasmonate signaling in Arabidopsis thaliana. It is proposed as a novel chemical tool for the analysis of MYC related jasmonate signaling.

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