Interaction of the Repressor Element 1-silencing Transcription Factor (REST) with Target Genes

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.

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Linking metabolic dysfunction with cardiovascular diseases: Brn-3b/POU4F2 transcription factor in cardiometabolic tissues in health and disease

Cell Death and Disease ◽

10.1038/s41419-021-03551-9 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Vishwanie S. Budhram-Mahadeo ◽

Matthew R. Solomons ◽

Eeshan A. O. Mahadeo-Heads

Keyword(s):

Transcription Factor ◽

Cardiovascular Diseases ◽

Cell Fate ◽

Target Genes ◽

Cardiovascular Responses ◽

Normal Function ◽

Valuable Insight ◽

Metabolic Dysfunction ◽

Pathological Changes ◽

Cardiac Responses

AbstractMetabolic and cardiovascular diseases are highly prevalent and chronic conditions that are closely linked by complex molecular and pathological changes. Such adverse effects often arise from changes in the expression of genes that control essential cellular functions, but the factors that drive such effects are not fully understood. Since tissue-specific transcription factors control the expression of multiple genes, which affect cell fate under different conditions, then identifying such regulators can provide valuable insight into the molecular basis of such diseases. This review explores emerging evidence that supports novel and important roles for the POU4F2/Brn-3b transcription factor (TF) in controlling cellular genes that regulate cardiometabolic function. Brn-3b is expressed in insulin-responsive metabolic tissues (e.g. skeletal muscle and adipose tissue) and is important for normal function because constitutive Brn-3b-knockout (KO) mice develop profound metabolic dysfunction (hyperglycaemia; insulin resistance). Brn-3b is highly expressed in the developing hearts, with lower levels in adult hearts. However, Brn-3b is re-expressed in adult cardiomyocytes following haemodynamic stress or injury and is necessary for adaptive cardiac responses, particularly in male hearts, because male Brn-3b KO mice develop adverse remodelling and reduced cardiac function. As a TF, Brn-3b regulates the expression of multiple target genes, including GLUT4, GSK3β, sonic hedgehog (SHH), cyclin D1 and CDK4, which have known functions in controlling metabolic processes but also participate in cardiac responses to stress or injury. Therefore, loss of Brn-3b and the resultant alterations in the expression of such genes could potentially provide the link between metabolic dysfunctions with adverse cardiovascular responses, which is seen in Brn-3b KO mutants. Since the loss of Brn-3b is associated with obesity, type II diabetes (T2DM) and altered cardiac responses to stress, this regulator may provide a new and important link for understanding how pathological changes arise in such endemic diseases.

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Differential activation mechanisms of two isoforms of Gcr1 transcription factor generated from spliced and un-spliced transcripts in Saccharomyces cerevisiae

Nucleic Acids Research ◽

10.1093/nar/gkaa1221 ◽

2020 ◽

Author(s):

Seungwoo Cha ◽

Chang Pyo Hong ◽

Hyun Ah Kang ◽

Ji-Sook Hahn

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcription Factor ◽

Target Genes ◽

Gene Encoding ◽

Metabolic Switch ◽

Differential Activation ◽

N Terminus ◽

Activation Mechanisms ◽

In Trans ◽

Separate Activation

Abstract Gcr1, an important transcription factor for glycolytic genes in Saccharomyces cerevisiae, was recently revealed to have two isoforms, Gcr1U and Gcr1S, produced from un-spliced and spliced transcripts, respectively. In this study, by generating strains expressing only Gcr1U or Gcr1S using the CRISPR/Cas9 system, we elucidate differential activation mechanisms of these two isoforms. The Gcr1U monomer forms an active complex with its coactivator Gcr2 homodimer, whereas Gcr1S acts as a homodimer without Gcr2. The USS domain, 55 residues at the N-terminus existing only in Gcr1U, inhibits dimerization of Gcr1U and even acts in trans to inhibit Gcr1S dimerization. The Gcr1S monomer inhibits the metabolic switch from fermentation to respiration by directly binding to the ALD4 promoter, which can be restored by overexpression of the ALD4 gene, encoding a mitochondrial aldehyde dehydrogenase required for ethanol utilization. Gcr1U and Gcr1S regulate almost the same target genes, but show unique activities depending on growth phase, suggesting that these isoforms play differential roles through separate activation mechanisms depending on environmental conditions.

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Analysis of steric effects in DamID profiling of transcription factor target genes

Genomics ◽

10.1016/j.ygeno.2017.01.006 ◽

2017 ◽

Vol 109 (2) ◽

pp. 75-82 ◽

Cited By ~ 4

Author(s):

Mirana Ramialison ◽

Ashley J. Waardenberg ◽

Nicole Schonrock ◽

Tram Doan ◽

Danielle de Jong ◽

...

Keyword(s):

Transcription Factor ◽

Target Genes ◽

Steric Effects ◽

Transcription Factor Target

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Sex- and Tissue-Specific Functions of Drosophila Doublesex Transcription Factor Target Genes

Developmental Cell ◽

10.1016/j.devcel.2014.11.021 ◽

2014 ◽

Vol 31 (6) ◽

pp. 761-773 ◽

Cited By ~ 65

Author(s):

Emily Clough ◽

Erin Jimenez ◽

Yoo-Ah Kim ◽

Cale Whitworth ◽

Megan C. Neville ◽

...

Keyword(s):

Transcription Factor ◽

Target Genes ◽

Tissue Specific ◽

Transcription Factor Target

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CHOP Enhancement of Gene Transcription by Interactions with Jun/Fos AP-1 Complex Proteins

Molecular and Cellular Biology ◽

10.1128/mcb.19.11.7589 ◽

1999 ◽

Vol 19 (11) ◽

pp. 7589-7599 ◽

Cited By ~ 95

Author(s):

Mariano Ubeda ◽

Mario Vallejo ◽

Joel F. Habener

Keyword(s):

Transcription Factor ◽

Gene Transcription ◽

Stress Responses ◽

Leucine Zipper ◽

Target Genes ◽

Cellular Stress ◽

Dominant Negative ◽

Dimerization Domain ◽

Mobility Shift

ABSTRACT The transcription factor CHOP (C/EBP homologous protein 10) is a bZIP protein induced by a variety of stimuli that evoke cellular stress responses and has been shown to arrest cell growth and to promote programmed cell death. CHOP cannot form homodimers but forms stable heterodimers with the C/EBP family of activating transcription factors. Although initially characterized as a dominant negative inhibitor of C/EBPs in the activation of gene transcription, CHOP-C/EBP can activate certain target genes. Here we show that CHOP interacts with members of the immediate-early response, growth-promoting AP-1 transcription factor family, JunD, c-Jun, and c-Fos, to activate promoter elements in the somatostatin, JunD, and collagenase genes. The leucine zipper dimerization domain is required for interactions with AP-1 proteins and transactivation of transcription. Analyses by electrophoretic mobility shift assays and by an in vivo mammalian two-hybrid system for protein-protein interactions indicate that CHOP interacts with AP-1 proteins inside cells and suggest that it is recruited to the AP-1 complex by a tethering mechanism rather than by direct binding of DNA. Thus, CHOP not only is a negative or a positive regulator of C/EBP target genes but also, when tethered to AP-1 factors, can activate AP-1 target genes. These findings establish the existence of a new mechanism by which CHOP regulates gene expression when cells are exposed to cellular stress.

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