Early Growth Response-1 (EGR-1) – A Key player in Myocardial Cell Injury

Ramadas, Nirupama; Rajaraman, Barathi; Kuppuswamy, Ashok A.; Vedantham, Srinivasan

doi:10.2174/1871525713666150123152131

Cited by 16 publications

(17 citation statements)

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“…Interestingly, although the group of transcription factors regulated by methylation was similar, the two strains showed different preference for the transcription factors whose target genes were most enriched for altered methylation (Online Table III; significance values compare enrichment of transcription factor binding motifs in the differentially methylated subset versus enrichment across the entire genome; only those factors with significant p values, expressed as –log, are shown): for instance, BUB/bnJ had preferential targeting of E2F-4 signaling, whereas BALB/cJ showed greater regulation of Egr-1 targets. As a transcriptional repressor, 23 E2F-4 would be expected to normally inhibit cell cycle/proliferative genes, whereas the Egr-1 family has been recently implicated in cardiac pathologies including hypertrophy, 24 although the mechanisms by which these factors choose their genomic targets is incompletely understood. Previous studies had implicated histone regulation 25 in altering transcription factor targeting, but this is the first evidence, to our knowledge, that either of these transcription factors are regulated by DNA modification.…”

Section: Resultsmentioning

confidence: 99%

DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated With Chromatin States

Chen

Orozco

Wang

et al. 2016

Circulation Research

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Rationale Only a small portion of the known heritability of cardiovascular diseases such as heart failure can be explained based on single gene mutations. Chromatin structure and regulation provide a substrate through which genetic differences in non-coding regions may impact cellular function and response to disease, but the mechanisms are unknown. Objective We conducted genome-wide measurements of DNA methylation in different strains of mice that are susceptible and resistant to isoproterenol-induced dysfunction to test the hypothesis that this epigenetic mark may play a causal role in the development of heart failure. Methods and Results BALB/cJ and BUB/BnJ mice, determined to be susceptible and resistant to isoproterenol-induced heart failure respectively, were administered the drug for 3 weeks via osmotic minipump. Reduced representational bisulfite sequencing was then used to compare the differences between the cardiac DNA methylome in the basal state between strains and then following isoproterenol treatment. Single base resolution DNA methylation measurements were obtained and revealed a bimodal distribution of methylation in the heart, enriched in lone intergenic CpGs and depleted from CpG islands around genes. Isoproterenol induced global decreases in methylation in both strains; however, the basal methylation pattern between strains shows striking differences that may be predictive of disease progression prior to environmental stress. The global correlation between promoter methylation and gene expression (as measured by microarray) was modest and revealed itself only with focused analyses of transcription start site and gene body regions (in contrast to when gene methylation was examined in toto). Modules of co-methylated genes displayed correlation with other protein-based epigenetic marks supporting the hypothesis that chromatin modifications act in a combinatorial manner to specify transcriptional phenotypes in the heart. Conclusions This study provides the first single base-resolution map of the mammalian cardiac DNA methylome and the first case-control analysis of the changes in DNA methylation with heart failure. The findings demonstrate marked genetic differences in DNA methylation that are associated with disease progression.

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Section: Resultsmentioning

confidence: 99%

DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated With Chromatin States

Chen

Orozco

Wang

et al. 2016

Circulation Research

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“…Egr-1 has emerged as a key regulator of cell growth, reproduction, and response to tissue injury (16,(61)(62)(63). Egr-1 was rapidly induced by interferons and pro-inflammatory cytokines such as TNF-α,…”

Section: Resultsmentioning

confidence: 99%

Regulation of early growth response-1 (Egr-1) gene expression by Stat1-independent type I interferon signaling and respiratory viruses

Ramana

2020

Preprint

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Respiratory virus infection is one of the leading causes of death in the world. Activation of the Jak-Stat pathway by interferon-alpha/beta (IFN-α/β) in lung epithelial cells is critical for innate immunity to respiratory viruses. Genetic and biochemical studies have shown that transcriptional regulation by IFN-α/β required the formation of interferon-stimulated gene factor-3 (ISGF-3) complex consisting of Stat1, Stat2, and Irf9 transcription factors. Furthermore, IFN-α/β receptor activates multiple signal transduction pathways in parallel to the Jak-Stat pathway and induces several transcription factors at mRNA levels resulting in the secondary and tertiary rounds of transcription. Transcriptional factor profiling in the transcriptome and RNA analysis revealed that Early growth response 1 (Egr-1) was rapidly induced by IFN-α/β and Toll-like receptor (TLR) ligands in multiple cell types. Studies in mutant cell lines lacking components of the ISGF-3 complex revealed that IFN-α/β induction of Egr-1 was independent of Stat1, Stat2, or Irf9. Activation of the Mek/Erk-1/2 pathway was implicated in the rapid induction of Egr-1 by IFN-α/β in serum-starved mouse lung epithelial cells. Interrogation of multiple microarray datasets revealed that respiratory viruses including coronaviruses regulated Egr-1 expression in human lung cell lines. Furthermore, Egr-1 inducible genes including transcription factors, mediators of cell growth, and chemokines were differentially regulated in the human lung cell lines after coronavirus infection, and in the lung biopsies of COVID-19 patients. Rapid induction by interferons, TLR ligands, and respiratory viruses suggests a critical role for Egr-1 in antiviral response and inflammation with potential implications for human health and disease.

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“…The EGR‐1 protein is the product of an immediate early gene , a key player in myocardial cell injury , and its expression is increased in heart failure . EGR‐1 supposedly functions as a master switch activated by ischaemia to trigger expression of pivotal regulators of inflammation, coagulation and vascular hyperpermeability .…”

Section: Discussionmentioning

confidence: 99%

The GRK2 Promoter Is Regulated by Early‐Growth Response Transcription Factor EGR‐1

Klenke

Engler

Ecker

et al. 2018

Basic Clin Pharma Tox

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The G-protein-coupled receptor kinase 2 (GRK2) plays a major role in cardiovascular diseases, and its expression is increased in heart failure. However, only little is known about factors being involved in up-regulation of GRK2 expression through transcriptional regulation of its promoter. Since the transcription factor early-growth response 1 (EGR-1) is also up-regulated in patients with heart failure, we tested the hypothesis that EGR-1 regulates GRK2 transcription. Stimulation of immortalized rat cardiomyocytes (H9c2) with phorbol 12-myristate 13-acetate (PMA) resulted in up-regulation of Egr-1 and subsequently of Grk2 mRNA expression, with maximum Grk2 expression (p = 0.008) 5 hr after PMA stimulation and being abolished by actinomycin D, indicating a transcriptional mechanism. To identify naturally occurring variants affecting promoter transcriptional activity, we identified a novel G(-43)A polymorphism (rs182084609), which surrounded a putative EGR-1-binding site. While the minor A allele frequency was rare (0.02), this variant was used to explore regulation by EGR-1 and promoter construct with altered alleles at nt-43 were subjected of reporter assays in human embryonic kidney cells (Hek293). Here, EGR-1 over-expression resulted in a more than twofold increase in GRK2 promoter activity but only in the presence of the G-allele (p = 0.04). In electrophoretic mobility shift assays, EGR-1 over-expression resulted in a specific binding of transcription factors only to the G oligonucleotide. Finally, EGR-1 over-expression resulted in increased GRK2 mRNA expression (p = 0.03). We identified EGR-1 as a regulator of GRK2 transcription. Suppression of GRK2 expression by inhibition of EGR-1 binding to GRK2 might be a promising approach to mitigate adrenergic desensitization.

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Early Growth Response-1 (EGR-1) – A Key player in Myocardial Cell Injury

Cited by 16 publications

References 0 publications

DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated With Chromatin States

DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated With Chromatin States

Regulation of early growth response-1 (Egr-1) gene expression by Stat1-independent type I interferon signaling and respiratory viruses

The GRK2 Promoter Is Regulated by Early‐Growth Response Transcription Factor EGR‐1

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