Changes in the Expression of Many Ets Family Transcription Factors and of Potential Target Genes in Normal Mammary Tissue and Tumors

Abstract PU.1 (Sfpi1) is an ets family transcription factor required for the proper generation of both myeloid (macrophages and neutrophils) and lymphoid lineages (B and T lymphocytes)(Scott 1994, McKercher 1996). Graded expression of exogenous PU.1 in murine PU.1-deficient fetal liver hematopoietic progenitors demonstrated that increased levels of PU.1 are required to initiate development of macrophages (DeKoter, 2000). We have studied the effects of graded expression of PU.1 on its occupancy in chromatin and on the development of myeloid cells in vitro. We measured changes in gene expression, PU.1 occupancy and histone modifications in PU.1-null hematopoietic progenitor cells stably expressing PU.1 fused to the ligand-binding domain of the estrogen receptor (PU.1-ER) (Walsh 2002). The level of active PU.1-ER was regulated with graded levels of the ER inducer tamoxifen. In vitro, intermediate levels of tamoxifen produced cells with granulocyte characteristics in the suspension cell fraction and macrophage-like characteristics in the attached fraction, whereas high levels of PU.1 produced mostly attached macrophage-like cells. Expression of granulocyte-specific PU.1 target mRNAs including gelatinase B (Mmp9) and myeloperoxidase (Mpo) were observed to be expressed only with intermediate levels of tamoxifen. In contrast, expression of macrophage PU.1 target mRNAs including Cd14, F4/80 and Cd68 mRNAs were observed to be gradually upregulated upon PU.1-ER activation, with the maximum expression at the highest levels of tamoxifen. Thus, the expression levels of PU.1 target genes and phenotypic characteristics of the cells are dependent on PU.1 levels. Interestingly, macrophage-like cells can be produced from granulocytic-like cells by changing tamoxifen levels and vice versa. Chromatin immunoprecipitation analysis revealed specific PU.1 occupancy within regulatory regions of the genes predominantly expressed in macrophages including Cd14 and Cd11b after treatment with high levels of tamoxifen. Specific PU.1 occupancy within regulatory regions of the granulocyte specific genes including MMP9 was observed at intermediate levels of tamoxifen. Suprisingly, chromatin immunoprecipitation analysis revealed specific PU.1 occupancy within regulatory regions of the lymphocytic PU.1 target genes including Interleukin-7 receptor (Il-7r) and RAG1 at intermediate levels of tamoxifen even though expression of these genes was not detected. Accumulation of acetylated K9 and methylated K4 of histone H3 in gene loci of macrophage and granulocytic markers such as Cd14, Cd11b, and Mmp9 correlated with their mRNA expression. However, lymphocyte-specific regulatory regions including that of Il-7r gene were hypoacetylated in H3K9 despite a marked PU.1 recruitment suggesting additional factors may be required for PU.1 mediated transactivation. To identify these molecules we have tested PU.1-dependent transcription factors: Egr2, Nab2, Cebpa and Gfi-1 and found that upon increasing PU.1 levels, expression of Egr2/Nab2 and Gfi-1/Cebpa changed in a reciprocal manner and these changes preceded expression of the lineage specific markers. We are currently testing if PU.1 directly regulates expression of Egr2, Nab2, Cebpa and Gfi-1 during granulocytic/macrophage differentiation.

Download Full-text

Golgi stress–induced transcriptional changes mediated by MAPK signaling and three ETS transcription factors regulate MCL1 splicing

Molecular Biology of the Cell ◽

10.1091/mbc.e17-06-0418 ◽

2018 ◽

Vol 29 (1) ◽

pp. 42-52 ◽

Cited By ~ 13

Author(s):

Jan Baumann ◽

Tatiana I. Ignashkova ◽

Sridhar R. Chirasani ◽

Silvia Ramírez-Peinado ◽

Hamed Alborzinia ◽

...

Keyword(s):

Transcription Factors ◽

Stress Responses ◽

Secretory Pathway ◽

Target Genes ◽

Enrichment Analysis ◽

Mapk Signaling ◽

Gene Set Enrichment Analysis ◽

Loss Of Function ◽

Control Of Gene Expression ◽

Ets Family

The secretory pathway is a major determinant of cellular homoeostasis. While research into secretory stress signaling has so far mostly focused on the endoplasmic reticulum (ER), emerging data suggest that the Golgi itself serves as an important signaling hub capable of initiating stress responses. To systematically identify novel Golgi stress mediators, we performed a transcriptomic analysis of cells exposed to three different pharmacological compounds known to elicit Golgi fragmentation: brefeldin A, golgicide A, and monensin. Subsequent gene-set enrichment analysis revealed a significant contribution of the ETS family transcription factors ELK1, GABPA/B, and ETS1 to the control of gene expression following compound treatment. Induction of Golgi stress leads to a late activation of the ETS upstream kinases MEK1/2 and ERK1/2, resulting in enhanced ETS factor activity and the transcription of ETS family target genes related to spliceosome function and cell death induction via alternate MCL1 splicing. Further genetic analyses using loss-of-function and gain-of-function experiments suggest that these transcription factors operate in parallel.

Download Full-text

Regulation of angiogenesis by ETS transcription factors

Biochemical Society Transactions ◽

10.1042/bst0371248 ◽

2009 ◽

Vol 37 (6) ◽

pp. 1248-1253 ◽

Cited By ~ 40

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.

Download Full-text

β-Neuregulin and Autocrine Mediated Survival of Schwann Cells Requires Activity of Ets Family Transcription Factors

Molecular and Cellular Neuroscience ◽

10.1006/mcne.2002.1109 ◽

2002 ◽

Vol 20 (1) ◽

pp. 154-167 ◽

Cited By ~ 23

Author(s):

David B. Parkinson ◽

Katrin Langner ◽

Soheila Sharghi Namini ◽

Kristjan R. Jessen ◽

Rhona Mirsky

Keyword(s):

Transcription Factors ◽

Schwann Cells ◽

Ets Family

Download Full-text

Regulatory Network Analysis in Estradiol-Treated Human Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22158193 ◽

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.

Download Full-text

Role of Satb1 and Satb2 Transcription Factors in the Glutamate Receptors Expression and Ca2+ Signaling in the Cortical Neurons In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms22115968 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5968

Author(s):

Egor A. Turovsky ◽

Maria V. Turovskaya ◽

Evgeniya I. Fedotova ◽

Alexey A. Babaev ◽

Viktor S. Tarabykin ◽

...

Keyword(s):

Transcription Factors ◽

Nmda Receptor ◽

Cortical Neurons ◽

Target Genes ◽

Cortical Cell ◽

Inhibitory System ◽

Selective Agonist ◽

Genes Encoding ◽

Deficient Mice

Transcription factors Satb1 and Satb2 are involved in the processes of cortex development and maturation of neurons. Alterations in the expression of their target genes can lead to neurodegenerative processes. Molecular and cellular mechanisms of regulation of neurotransmission by these transcription factors remain poorly understood. In this study, we have shown that transcription factors Satb1 and Satb2 participate in the regulation of genes encoding the NMDA-, AMPA-, and KA- receptor subunits and the inhibitory GABA(A) receptor. Deletion of gene for either Satb1 or Satb2 homologous factors induces the expression of genes encoding the NMDA receptor subunits, thereby leading to higher amplitudes of Ca2+-signals in neurons derived from the Satb1-deficient (Satb1fl/+ * NexCre/+) and Satb1-null mice (Satb1fl/fl * NexCre/+) in response to the selective agonist reducing the EC50 for the NMDA receptor. Simultaneously, there is an increase in the expression of the Gria2 gene, encoding the AMPA receptor subunit, thus decreasing the Ca2+-signals of neurons in response to the treatment with a selective agonist (5-Fluorowillardiine (FW)). The Satb1 deletion increases the sensitivity of the KA receptor to the agonist (domoic acid), in the cortical neurons of the Satb1-deficient mice but decreases it in the Satb1-null mice. At the same time, the Satb2 deletion decreases Ca2+-signals and the sensitivity of the KA receptor to the agonist in neurons from the Satb1-null and the Satb1-deficient mice. The Satb1 deletion affects the development of the inhibitory system of neurotransmission resulting in the suppression of the neuron maturation process and switching the GABAergic responses from excitatory to inhibitory, while the Satb2 deletion has a similar effect only in the Satb1-null mice. We show that the Satb1 and Satb2 transcription factors are involved in the regulation of the transmission of excitatory signals and inhibition of the neuronal network in the cortical cell culture.

Download Full-text

High Energy Intake Induced Overexpression of Transcription Factors and Its Regulatory Genes Involved in Acceleration of Hepatic Lipogenesis: A Rat Model for Type 2 Diabetes

Biomedicines ◽

10.3390/biomedicines7040076 ◽

2019 ◽

Vol 7 (4) ◽

pp. 76 ◽

Cited By ~ 3

Author(s):

Suresh P. Khadke ◽

Aniket A. Kuvalekar ◽

Abhay M. Harsulkar ◽

Nitin Mantri

Keyword(s):

Type 2 Diabetes ◽

Transcription Factors ◽

Glucose Tolerance ◽

Molecular Mechanisms ◽

Target Genes ◽

High Energy ◽

Tolerance Test ◽

Diabetic Control ◽

Ppar Γ

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by impaired insulin action and its secretion. The objectives of the present study were to establish an economical and efficient animal model, mimicking pathophysiology of human T2DM to understand probable molecular mechanisms in context with lipid metabolism. In the present study, male Wistar rats were randomly divided into three groups. Animals were fed with high fat diet (HFD) except healthy control (HC) for 12 weeks. After eight weeks, intra peritoneal glucose tolerance test was performed. After confirmation of glucose intolerance, diabetic control (DC) group was injected with streptozotocin (STZ) (35 mg/kg b.w., i.p.). HFD fed rats showed increase (p ≤ 0.001) in glucose tolerance and HOMA-IR as compared to HC. Diabetes rats showed abnormal (p ≤ 0.001) lipid profile as compared to HC. The hepatocyte expression of transcription factors SREBP-1c and NFκβ, and their target genes were found to be upregulated, while PPAR-γ, CPT1A and FABP expressions were downregulated as compared to the HC. A number of animal models have been raised for studying T2DM, but the study has been restricted to only the biochemical level. The model is validated at biochemical, molecular and histopathological levels, which can be used for screening new therapeutics for the effective management of T2DM.

Download Full-text

Mechanistic Heterogeneity in Site Recognition by the Structurally Homologous DNA-binding Domains of the ETS Family Transcription Factors Ets-1 and PU.1

Journal of Biological Chemistry ◽

10.1074/jbc.m114.575340 ◽

2014 ◽

Vol 289 (31) ◽

pp. 21605-21616 ◽

Cited By ~ 18

Author(s):

Shuo Wang ◽

Miles H. Linde ◽

Manoj Munde ◽

Victor D. Carvalho ◽

W. David Wilson ◽

...

Keyword(s):

Transcription Factors ◽

Dna Binding ◽

Dna Binding Domains ◽

Binding Domains ◽

Ets Family ◽

Site Recognition

Download Full-text

Screening Driving Transcription Factors in the Processing of Gastric Cancer

Gastroenterology Research and Practice ◽

10.1155/2016/8431480 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 5

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.

Download Full-text