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Gene regulation in the immediate-early response process
Open accessAbstract
Immediate-early genes (IEGs) can be activated and transcribed within minutes after stimulation, without the need for de novo protein synthesis, and they are stimulated in response to both cell-extrinsic and cell-intrinsic signals. Extracellular signals are transduced from the cell surface, through receptors activating a chain of proteins in the cell, in particular extracellular-signal-regulated kinases (ERKs), mitogen-activated protein kinases (MAPKs) and members of the RhoA-actin pathway. These communicate through a signaling cascade by adding phosphate groups to neighboring proteins, and this will eventually activate and translocate TFs to the nucleus and thereby induce gene expression. The gene activation also involves proximal and distal enhancers that interact with promoters to simulate gene expression. The immediate-early genes have essential biological roles, in particular in stress response, like the immune system, and in differentiation. Therefore they also have important roles in various diseases, including cancer development. In this paper we summarize some recent advances on key aspects of the activation and regulation of immediate-early genes.
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“suggesting that acute social defeat stress induces a transient but robust inflammatory response that contributes to short-term behavioral and physiological changes”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [45]
In the citing paper
“these are known to regulate neuronal activity and inflammatory responses under stress conditions”
From Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress (2025) · cites this paper as [45]
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Bladder Exposure to Gardnerella Activates Host Pathways Necessary for Escherichia coli Recurrent UTI
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“Notably, all of the upregulated genes (Atf3, Fosb, Nur77, Nurr1 and Arc) belong to the class of Immediate Early (IE) response genes that are rapidly co-induced in multiple cell types in response to external stimuli, such as infection and inflammatory signals (Wilson et al., 2010; Bahrami and Drablos, 2016; Crean and M…”
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“Such mechanisms include but are not restricted to: selective epigenetic and/or microRNA-mediated silencing of IEGs, selective IEG protein degradation, selective inhibition of IEG proteins by repressors (for review, see (3)).”
BackgroundInfluentialThe Immediate Early Response of Lens Epithelial Cells to Lens Injury
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“IEGs are transcriptionally induced within minutes in response to growth factor stimulation, and many IEGs follow a transient expression pattern that is terminated by a combination of transcriptional shut-off and rapid mRNA decay [82].”
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“Cluster 2 was characterized by high expression of immediate early genes (Jun, Fos, Egr1, Klf2, and Aft3) encoding transcription factors [37] and annotated as immediate early response macrophages (IER MΦs).”
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“Therefore, to consider the response at a gene expression level, we selected exercise-induced genes based on the next criterion comprising two points: (1) a functional role of this gene in the regulation of skeletal muscle metabolism is known; (2) its expression in human skeletal muscle markedly changes in response to…”
BackgroundMethodLatency Reversing Agents: Kick and Kill of HTLV-1?
Schnell, A. P., Kohrt, S., & Thoma‐Kress, A. K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115545 · Cited by 22
“MAPKs induce the expression of immediate-early genes (IEGs).”
BackgroundEmbryonic stem cells become mechanoresponsive upon exit from ground state of pluripotency
Verstreken, C. M., Labouesse, C., Agley, C. C., & Chalut, K. J. (2019) · Open Biology · doi:10.1098/rsob.180203 · Cited by 16
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“A unique group of genes rapidly and transiently transcribed in response to extracellular stimuli in the absence of de novo protein synthesis, leading to quick, adaptive changes in cellular function, are known as immediate early genes (IEGs; Bahrami & Drabløs, 2016).”
BackgroundFormation of nuclear condensates by the Mediator complex subunit Med15 in mammalian cells
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“IEGs respond very rapidly to a variety of cell-extrinsic and cellintrinsic signals, including serum, growth factors, cytokines, and UV radiation [30, 31].”
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Signal-induced PARP1-Erk synergism mediates IEG expression
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EGR1 drives cell proliferation by directly stimulating TFEB transcription in response to starvation
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“EGR1 belongs to the immediate-early genes (IEGs) family and represents the earliest downstream nuclear target sensitive to changes in the extracellular environment, including nutrients and stress signals [29], which triggers its activation via the MEK1/2/ ERK signaling pathway [21,30].”
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“In addition, this upregulation should be independent of de novo protein synthesis (Bahrami & Drabløs, 2016; Fowler et al., 2011; Mehendale & Apte, 2009).”
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Cytogenetic, Genomic, and Functional Characterization of Pituitary Gonadotrope Cell Lines
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“Differences in patterns of gene expression and GnRH regulation could partially be attributed to variations in gene CN; gene or promoter mutations; alterations in the expression of transcription factors, transcriptional regulators, or upstream intracellular signaling molecules; variations in promoter methylation patter…”
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“…toxicity, c‐fos, was significantly induced by N‐acetyl‐p‐ aminophenol treatment irrespective of recombinant human thioredoxin pretreatment c‐fos has been postulated as an immediate response gene and cell suffering marker in the liver after exposing to liver toxicants (Bahrami & Drablos, 2016).”
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“Moreover, the gene expression profiles of these cells correlated with the activity of transcription factors (TFs) within the AP - 1 pathway, ATF1/2/4, JUN, and FOS (Fig.”
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“The IEGs have essential biological roles in environmental signals and stress response; therefore, they might also have important roles in various diseases, including cancer development [8].”
BackgroundPost-transcriptional checkpoints in autoimmunity
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“To validate the importance of the expression of IEGs for the capacity of SG stem cells to form SGOs, PIC-cultured SGOs were exposed in vitro to the β-adrenergic agonist isoproterenol, known to activate multiple signalling pathways involved in IEG expression (Yeh et al., 2012; Bahrami and Drabløs, 2016).”
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“Disruptions in IEG transcriptional regulation are closely related to various neurological disorders (26,27).”
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“Moreover, we selected a list of eight genes (FOS, FOSB, JUN, NR4A1, NR4A2, MCL1, ATF3, EGR1) which have been identified as immediate early genes (IEGs) across several publications [13, 35].”
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“In this pattern, as expected, gene induction is more efficient in K57N cells than in K53S cells; (2) sigmoidal-A, where the gene expression was enhanced vs.”
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“ERK1/2, p38, JNK, but not PI3K mediate catecholoestradiol-induced proliferation Mitogen activated protein kinases and PI3K belong to the family of Immediate-early genes, which are genes that can be activated and transcribed within minutes of receptor stimulation (Bahrami & Drablos, 2016).”
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“…and primary response genes such as PDGF-BB, TREM1, HDAC, NUPR1, STAT3, EGF, TNF, ERK, IL1b, and JUN within a 20–60-minute timeframe post-injury [16]; 2) The initiation of specific MAPK pathways, including ERK, p38, MAPK, the atypical ERK5, JNK, PKA, and cAMP-related cascades; 3) The…”
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“Most IEGs encode transcription factors that regulate genes involved in various cell functions in normal cell growth and differentiation, intracellular information transmission and energy metabolism [8].”
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“dynamics similar to those observed for primary response genes [65,74,75].”
ResultThe role of polo‐like kinase 3 in the response of BRAF‐mutant cells to targeted anticancer therapies
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Amyloid-β-driven Alzheimer’s disease reshapes the colonic immune system in mice
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“IEGs can be induced by distinct pathways, including RhoA, ERK and p38 [71,72].”
BackgroundPatiño-Martínez, E., Solís-Barbosa, M. A., Santana, E., González-Domínguez, É., Segovia-gamboa, N., Meraz-Ríos, M., Córdova, E., Valdés, J., Corbí, Á., & Sánchez-Torres, C. (2022) · Immunobiology · doi:10.1016/j.imbio.2022.152299 · Cited by 12
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“The immediate early genes are activated transiently and rapidly in response to various stimuli, and mediate diverse signaling pathways [18].”
BackgroundCollateral cleavage of 28s rRNA by RfxCas13d causes death of mice
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“There are 294 several pathways that lead to the activation of IEGs, such as the RhoA-actin and the ERK, JNK 295 and p38 MAPK pathways([31]).”
BackgroundXu, C., Zhang, M., Zu, L., Zhang, P., Sun, L., Liu, X., & Fang, M. (2021) · Aging · doi:10.18632/aging.203118 · Cited by 14
“IEGs, such as activity-regulated cytoskeleton-associated protein (ARC), neuronal Per/Arnt/Sim domain protein 4 (NPAS4), early growth response protein 1 (EGR1), and brain-derived neurotrophic factor (BDNF), are subsets of genes induced by stimuli in seconds [11].”
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“These genes are known to be immediate-early genes, whose activation and transcription usually occur within few minutes after stimulation by extracellular or intracellular signals (Bahrami and Drabløs, 2016).”
BackgroundShi, J.-W., Folwaczny, M., Wichelhaus, A., & Baumert, U. (2019) · Orthodontics & craniofacial research · doi:10.1111/ocr.12307 · Cited by 12
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“…and Fosl2 , was observed; these are known to regulate neuronal activity and inflammatory responses under stress conditions, suggesting that acute social defeat stress induces a transient but robust inflammatory response that contributes to short-term behavioral and physiological changes [44,45].”
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“, NMDAR), neurotransmitters (glutamine, dopamine), and viral infection (Bahrami and Drabløs, 2016; Minatohara et al., 2016; Gallo et al., 2018).”
BackgroundMachuka, E., Juma, J., Muigai, A. W. T., Amimo, J. O., Pellé, R., & Abworo, E. O. (2022) · BMC Genomics · doi:10.1186/s12864-022-08754-8 · Cited by 13
Identifying General Tumor and Specific Lung Cancer Biomarkers by Transcriptomic Analysis
Otálora-Otálora, B. A., Osuna-Garzón, D. A., Carvajal-Parra, M. S., Cañas, A., Montecino, M. A., López-Kleine, L., & Rojas, A. P. (2022) · Biology · doi:10.3390/biology11071082 · Cited by 10
“differentiation, survival, and death through the activation or repression of a group of genes called immediate early genes (IEGs) [14].”
BackgroundEstablishment of Host–Algal Endosymbioses: Genetic Response to Symbiont Versus Prey in a Sponge Host
Geraghty, S., Koutsouveli, V., Hall, C., Chang, L., Sacristán-Soriano, O., Hill, M., Riesgo, A., & Hill, A. (2021) · Genome Biology and Evolution · doi:10.1093/gbe/evab252 · Cited by 11
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“Transient activation and regulation of immediate-early genes are considered primary cellular responses to an external signal in cancer development (10).”
BackgroundPeripheral Neuronal Activation Shapes the Microbiome and Alters Gut PhysiologyPreprint
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Microfluidic reactors for advancing the MS analysis of fast biological responses
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Epigenome Interactions with Patterned Neuronal Activity
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“This rapid transcription occurs through activation of specific transcription factors (Bahrami and Drabløs 2016), the most widely studied being phosphorylation of the calcium-responsive transcription factor CREB (Pham and others 2000).”
Distinct mechanisms of transcriptomic habituation to repeated stress in the mouse hippocampus
Waag, R., von Ziegler, L., Sonder, E., Sturman, O., Leonardi, J., Frei, S., Longster, R., Gapp, K., Germain, P., & Bohacek, J. (2025) · Nature Communications · doi:10.1038/s41467-025-67825-y · Cited by 11
“We observe that the members of cluster 1 are strongly enriched for CREB1 and SRF transcription factor activity, both crucial for IEG induction 56 .”
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“Genes that exhibit such rapid changes in gene expression in response to a stimulus are often called “ early response genes ” 41,42 or “ immediate early response genes ” 5,43 .”
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“Recently, Lavrynenko et al. revealed that D. melanogaster only synthesized C28 ecdysteroids when they were reared on LDM with C28 or C29 dietary sterols [3].”
BackgroundInfluentialSystematic identification of NF90 target RNAs by iCLIP analysis
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“These early response genes include immediate-early genes (IEGs) that are conserved across cell types and are rapidly activated by diverse environmental stimuli (Bahrami and Drablos, 2016; Fowler et al., 2011).”
BackgroundInfluentialShort-term transcriptomic response to plasma membrane injury
Häger, S. C., Dias, C., Sønder, S. L., Olsen, A., da Piedade, I., Heitmann, A. S. B., Papaleo, E., & Nylandsted, J. (2021) · Scientific Reports · doi:10.1038/s41598-021-98420-y · Cited by 10
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“Fos proto-oncogene (FOS), early growth response 1 (EGR1), and early growth response 2 (EGR2) are transcription factors known as immediate-early genes (IEGs), i.e., they are able to respond very quickly to regulatory signals, for example, in immune responses (reviewed in Bahrami and Drablos, 2016).”
BackgroundAdaptation trajectories during adhesion and spreading affect future cell states
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Regulation of NR4A2 Gene Expression and Its Importance in Neurodegenerative and Psychiatric Diseases
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“Furthermore, IEGs respond to a variety of extrinsic and intrinsic stimuli in diverse cell types, suggesting a general response mechanism [32,33].”
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Medina‐Ruiz, L., Bartolini, R., Mathie, H. A., Halawa, H. A., Cunningham, M. E., & Graham, G. J. (2024) · The Journal of Immunology · doi:10.4049/jimmunol.2400007 · Cited by 9
“It is possible that this represents an immediate early response (26) in this monocyte population, which is triggered as they enter the cell cycle, and that quiescent cells, or cells in G 1 , do not express the neutrophil-associated genes.”
Metadata
- Authors
- Bahrami, S., & Drabløs, F.
- Affiliations
- Norwegian University of Science and Technology (NO)
- Corresponding author
- Drabløs, Finn
- Venue
- Advances in Biological Regulation
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 62
- Pages
- 37-49
- ISSN
- 2212-4926 (ISSN-L)
- OpenAlex
- W2349918789
- Cited by
- 465
- References
- 109
- Citations by year
- 2026: 49 · 2025: 50 · 2024: 40 · 2023: 50 · 2022: 65 · 2021: 64 · 2020: 42 · 2019: 44 · 2018: 36 · 2017: 20 · 2016: 5
- FWCI
- 3.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Advances in Biological Regulation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Helse Midt-Norge
- Norges Teknisk-Naturvitenskapelige Universitet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- immediate early genes, gene expression regulation, transcription factor activation, MAPK signaling, ERK, signal transduction, enhancers, promoter regulation, stress response, immune response, cell differentiation, cancer
- MeSH terms
- Actins, Animals, Cell Differentiation, Cell Nucleus, Eukaryotic Cells, Gene Expression Regulation, Humans, Phosphorylation, Promoter Regions, Genetic, Transcription Factors, Signal Transduction, Genes, Immediate-Early, rhoA GTP-Binding Protein, Mitogen-Activated Protein Kinases, Extracellular Signal-Regulated MAP Kinases
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