scholarly journals GATA3 mutation disrupts a functional network governed by estrogen receptor, FOXA1 and GATA3

2019 ◽  
Author(s):  
Motoki Takaku ◽  
Sara A. Grimm ◽  
Bony De Kumar ◽  
Brian D. Bennett ◽  
Paul A. Wade
Keyword(s):  
Transcription Factors ◽  
Regulatory Network ◽  
Genomic Analysis ◽  
Active Role ◽  
Cooperative Action ◽  
Er Positive ◽  
17Β Estradiol ◽  
Differential Gene ◽  
Gata3 Mutation ◽  
Mutant Cells

AbstractEstrogen receptors (ER) are part of the nuclear receptor superfamily of transcription factors and are activated by the steroid hormone 17β-estradiol. ER forms a regulatory network in conjunction with other transcription factors, such as FOXA1 and GATA3. GATA3 has been identified as one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER. How GATA3 mutations impact this transcriptional network is unknown. Here we investigate the function of one of the recurrent patient-derived GATA3 mutations (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt the cooperative action of ER, FOXA1, and GATA3, and induce a change in chromatin localization of these factors. Relocalization of ER and FOXA1 is associated with altered chromatin architecture, which leads to differential gene expression in GATA3 mutant cells. These results suggest an active role for GATA3 mutants in ER positive breast tumors.

scholarly journals Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yichao Li ◽  
Sushil K. Jaiswal ◽  
Rupleen Kaur ◽  
Dana Alsaadi ◽  
Xiaoyu Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Transcription Factors ◽  
Epithelial Ovarian Cancer ◽  
Differential Gene Expression ◽  
Regulatory Network ◽  
Regulatory Factors ◽  
Cancer Subtypes ◽  
Differential Gene ◽  
Er Alpha

Abstract Background The heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in their biological features, invasiveness, and response to chemotherapy, but the transcriptional regulators causing their differences remain nebulous. Methods In this study, we compared high-grade serous ovarian cancers (HGSOCs) to low malignant potential or serous borderline tumors (SBTs). Our aim was to discover new regulatory factors causing distinct biological properties of HGSOCs and SBTs. Results In a discovery dataset, we identified 11 differentially expressed genes (DEGs) between SBTs and HGSOCs. Their expression correctly classified 95% of 267 validation samples. Two of the DEGs, TMEM30B and TSPAN1, were significantly associated with worse overall survival in patients with HGSOC. We also identified 17 DEGs that distinguished stage II vs. III HGSOC. In these two DEG promoter sets, we identified significant enrichment of predicted transcription factor binding sites, including those of RARA, FOXF1, BHLHE41, and PITX1. Using published ChIP-seq data acquired from multiple non-ovarian cell types, we showed additional regulatory factors, including AP2-gamma/TFAP2C, FOXA1, and BHLHE40, bound at the majority of DEG promoters. Several of the factors are known to cooperate with and predict the presence of nuclear hormone receptor estrogen receptor alpha (ER-alpha). We experimentally confirmed ER-alpha and PITX1 presence at the DEGs by performing ChIP-seq analysis using the ovarian cancer cell line PEO4. Finally, RNA-seq analysis identified recurrent gene fusion events in our EOC tumor set. Some of these fusions were significantly associated with survival in HGSOC patients; however, the fusion genes are not regulated by the transcription factors identified for the DEGs. Conclusions These data implicate an estrogen-responsive regulatory network in the differential gene expression between ovarian cancer subtypes and stages, which includes PITX1. Importantly, the transcription factors associated with our DEG promoters are known to form the MegaTrans complex in breast cancer. This is the first study to implicate the MegaTrans complex in contributing to the distinct biological trajectories of malignant and indolent ovarian cancer subtypes.

scholarly journals Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3

2020 ◽  
Vol 48 (9) ◽  
pp. 4756-4768 ◽  
Author(s):  
Motoki Takaku ◽  
Sara A Grimm ◽  
Bony De Kumar ◽  
Brian D Bennett ◽  
Paul A Wade
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Regulatory Network ◽  
Cell Biology ◽  
Estrogen Receptor Alpha ◽  
Transcriptional Regulatory Network ◽  
Genomic Analysis ◽  
Receptor Alpha ◽  
Mutant Cells

Abstract Estrogen receptors (ER) are activated by the steroid hormone 17β-estradiol. Estrogen receptor alpha (ER-α) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER-α. How GATA3 mutations found in breast cancer impact genomic localization of ER-α and the transcriptional network downstream of ER-α and FOXA1 remains unclear. Here, we investigate the function of a recurrent patient-derived GATA3 mutation (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt localization of ER-α and FOXA1. Loci co-bound by all three factors are enriched for genes integral to mammary gland development as well as epithelial cell biology. This gene set is differentially regulated in GATA3 mutant cells in culture and in tumors bearing similar mutations in vivo. The altered distribution of ER-α and FOXA1 in GATA3-mutant cells is associated with altered chromatin architecture, which leads to differential gene expression. These results suggest an active role for GATA3 zinc finger 2 mutants in ER-α positive breast tumors.

Comparative analysis of conservation and regulatory network on core transcription factors in mouse inner ear development

2013 ◽  
Vol 35 (10) ◽  
pp. 1198-1208
Author(s):  
Zhi-Qiang CHEN ◽  
Xin-Huan HAN ◽  
Qin-Jun WEI ◽  
Guang-Qian XING ◽  
Xin CAO
Keyword(s):  
Transcription Factors ◽  
Comparative Analysis ◽  
Inner Ear ◽  
Regulatory Network ◽  
Ear Development ◽  
Inner Ear Development

scholarly journals NKL Homeobox Gene VENTX Is Part of a Regulatory Network in Human Conventional Dendritic Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 5902
Author(s):  
Stefan Nagel ◽  
Claudia Pommerenke ◽  
Corinna Meyer ◽  
Hans G. Drexler
Keyword(s):  
Dendritic Cells ◽  
Transcription Factors ◽  
Cell Lines ◽  
Expression Profiling ◽  
Regulatory Network ◽  
Homeobox Gene ◽  
Leukemia Cell Line ◽  
Specific Gene ◽  
Rna Seq ◽  
And Function

Recently, we documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in human myelopoiesis including monocytes and their derived dendritic cells (DCs). Here, we enlarge this map to include normal NKL homeobox gene expressions in progenitor-derived DCs. Analysis of public gene expression profiling and RNA-seq datasets containing plasmacytoid and conventional dendritic cells (pDC and cDC) demonstrated HHEX activity in both entities while cDCs additionally expressed VENTX. The consequent aim of our study was to examine regulation and function of VENTX in DCs. We compared profiling data of VENTX-positive cDC and monocytes with VENTX-negative pDC and common myeloid progenitor entities and revealed several differentially expressed genes encoding transcription factors and pathway components, representing potential VENTX regulators. Screening of RNA-seq data for 100 leukemia/lymphoma cell lines identified prominent VENTX expression in an acute myelomonocytic leukemia cell line, MUTZ-3 containing inv(3)(q21q26) and t(12;22)(p13;q11) and representing a model for DC differentiation studies. Furthermore, extended gene analyses indicated that MUTZ-3 is associated with the subtype cDC2. In addition to analysis of public chromatin immune-precipitation data, subsequent knockdown experiments and modulations of signaling pathways in MUTZ-3 and control cell lines confirmed identified candidate transcription factors CEBPB, ETV6, EVI1, GATA2, IRF2, MN1, SPIB, and SPI1 and the CSF-, NOTCH-, and TNFa-pathways as VENTX regulators. Live-cell imaging analyses of MUTZ-3 cells treated for VENTX knockdown excluded impacts on apoptosis or induced alteration of differentiation-associated cell morphology. In contrast, target gene analysis performed by expression profiling of knockdown-treated MUTZ-3 cells revealed VENTX-mediated activation of several cDC-specific genes including CSFR1, EGR2, and MIR10A and inhibition of pDC-specific genes like RUNX2. Taken together, we added NKL homeobox gene activities for progenitor-derived DCs to the NKL-code, showing that VENTX is expressed in cDCs but not in pDCs and forms part of a cDC-specific gene regulatory network operating in DC differentiation and function.

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.

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 Fuzzy modeling reveals a dynamic self-sustaining network of the GLI transcription factors controlling important metabolic regulators in adult mouse hepatocytes

2015 ◽  
Vol 11 (8) ◽  
pp. 2190-2197 ◽  
Author(s):  
Wolfgang Schmidt-Heck ◽  
Madlen Matz-Soja ◽  
Susanne Aleithe ◽  
Eugenia Marbach ◽  
Reinhard Guthke ◽  
...  
Keyword(s):  
Fuzzy Logic ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Adult Mouse ◽  
Dynamic Features ◽  
Hedgehog Signalling ◽  
Gli Transcription Factors ◽  
Mouse Hepatocytes ◽  
Metabolic Regulators ◽  
Modelling Approach

The Hedgehog signalling-driven Gli transcription factors in hepatocytes form a regulatory network identified by a fuzzy-logic modelling approach. The network explains dynamic features important for hepatocyte function and fate.

Characterization of a mutated KCNJ5 gene, G387R, in unilateral primary aldosteronism

2021 ◽  
Vol 67 (4) ◽  
pp. 203-215
Author(s):  
Jeff S Chueh ◽  
Kang-Yung Peng ◽  
Vin-Cent Wu ◽  
Shuo-Meng Wang ◽  
Chieh-Kai Chan ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Bioinformatics Analysis ◽  
Genomic Analysis ◽  
Ion Current ◽  
Mutant Channel ◽  
Transfected Cells ◽  
Aldosterone Production ◽  
Mutant Cells ◽  
Electrophysiological Experiment

Somatic mutation in the KCNJ5 gene is a common driver of autonomous aldosterone overproduction in aldosterone-producing adenomas (APA). KCNJ5 mutations contribute to a loss of potassium selectivity, and an inward Na+ current could be detected in cells transfected with mutated KCNJ5. Among 223 unilateral primary aldosteronism (uPA) individuals with a KCNJ5 mutation, we identified 6 adenomas with a KCNJ5 p.Gly387Arg (G387R) mutation, previously unreported in uPA patients. The six uPA patients harboring mutant KCNJ5-G387R were older, had a longer hypertensive history, and had milder elevated preoperative plasma aldosterone levels than those APA patients with more frequently detected KCNJ5 mutations. CYP11B2 immunohistochemical staining was only positive in three adenomas, while the other three had co-existing multiple aldosterone-producing micronodules. The bioinformatics analysis predicted that function of the KCNJ5-G387R mutant channel could be pathological. However, the electrophysiological experiment demonstrated that transfected G387R mutant cells did not have an aberrantly stimulated ion current, with lower CYP11B2 synthesis and aldosterone production, when compared to that of the more frequently detected mutant KCNJ5-L168R transfected cells. In conclusion, mutant KCNJ5-G387R is not a functional KCNJ5 mutation in unilateral PA. Compared with other KCNJ5 mutations, the observed mildly elevated aldosterone expression actually hindered the clinical identification of clinical unilateral PA. The KCNJ5-G387R mutation needs to be distinguished from functional KCNJ5 mutations during genomic analysis in APA evaluation because of its functional silence.

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