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User:Biubiu44/Immediate early genes

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Immediate early genes (IEGs) are genes that are activated transiently and rapidly in response to a wide variety of cellular stimuli. They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli before any new proteins are synthesized. IEGs are distinct from "late response" genes, which can only be activated later, following the synthesis of early response gene products. Thus IEGs have been called the "gateway to the genomic response". The term can describe viral regulatory proteins that are synthesized following viral infection of a host cell, or cellular proteins that are made immediately following stimulation of a resting cell by extracellular signals.

In their role as "gateways to genomic response", many IEG products are naturally transcription factors or other DNA-binding proteins. However, other important classes of IEG products include secreted proteins, Cytoskeleton, and receptor subunits. Neuronal IEGs are used prevalently as a marker to track brain activaties in the context of memory formation and development of psychiatric disorders.[1] IEGs are also of interest as a therapeutic target for treatment of human cytomegalovirus.[2]

Overview

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A study from 1998 identified around 40 IEGs[3] though more recent studies sometimes find more, or cell-type-specific IEGs. The earliest known and best characterized include c-fos, c-myc, and c-jun, genes that were found to be homologous to retroviral oncogenes. Thus IEGs are well known as early regulators of cell growth and differentiation signals. However, other findings suggest roles for IEGs in many other cellular processes.

Expression of IEGs occurs in response to internal and external cell signals, occurring rapidly without the need to synthesis new transcription factors.[4] The genomic sequence of IEGs are generally shorter in length (~19kb) and exhibits an enrichment of specific transcription factor binding sites, offering redundancy in transcription initiation.[5] Translation of IEG mRNA into proteins occurs regardless of protein synthesis inhibitors which disrupts the process of protein production.[6] Rapid expression of IEGs are also attributed to the accessibility of its promotor sequence through histone acetylation thats consistent pre- and post-expression.[5] Downregulation of mRNA transcription occurs through redundent targeting of the 3' UTR region by microRNAs, resulting in translational repression and degradation. The expression of IEG protein is often transient due to rapid mRNA downregulation and increased proteolysis of translated products.[5]

Functions

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Activation of gene transcription is a complex system of signal cascades and recruitment of necessary components such as RNA polymerase and transcription factors. IEGs are often the first responders to regulatory signals with many reaching peak expression within 30 minutes after stimuli compared to 2-4 hours in the case of delayed primary response gene.[7] There are many singaling pathways leading to the activation of IEGs, many of which (MAPK/ERK, PI3K, etc) are studied in the context of cancer.[5] As such, many IEGs function as transcription factors regulating expression of downstream genes or are proto-oncogenes associated with altered cell growth.[7]

Research Applications

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The majority of research surrounding IEGs expression is studied in the context of neuronal activity, specifically memory formation, neuropsychiatric diseases, and behavioral activities. [8] Immediate early genes present in the brain are associated with a range of functions such as modifying synaptic functions through transient and rapid activation growth factors or the expression of cellular proteins. [9] These changes are theorized to be the means in which memory is stored in the brain as outline in the cofncept of memory trace or engram. In the context of neuropsychiatric diseases, up-regulation of certain IEGs related to the formation of fear-related memories contribute to the development of a variety of disease such as: Schizophrenia, Panic disorder, Post-traumatic stress disorder…[10]

Memory Formation

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Some IEGs such as ZNF268 and Arc have been implicated in learning, memory and long-term potentiation.[11][12]

 
Expression of IEG c-Fos in neurons responding to stimulation with potassium treatment.

A wide range of neuronal stimulation have been shown to induce IEG expression ranging from sensory and behavioral to drug-induced convulsions.[8] As such, IEGs are utilized as a marker to understand neuronal ensembles associated with formations of certain memories such as fear, commonly attributed to the development of psychiatric disorders.[10]For example, neurons expression Arc in the hippocampus show phenotypic and behavioral differences in response to stimuli such as altered dendritic spine morphology or spontaneous firing rate.[8] This association suggests the expression of certain IEGs in response to a stimulus results in expansion of the related neuronal circuit by incorporating the activated neuron assembles. Other IEGs effect different neural properties with knock out of Arc showing adverse affects on the formation of long-term memory.[8] These findings offer insight into the molecular mechanism and functional changes brought about by IEG expression, expanding the theory of memory trace.

Memory consolidation during a learning experience depends on the rapid expression of a set of IEGs in brain neurons.[13] In general, expression of genes often can be epigenetically repressed by the presence of 5-methylcytosine in the DNA promoter regions of the genes. However in the case of IEGs associated with memory consolidation, demethylation of 5-methylcytosine to form the normal base cytosine can induce rapid gene expression. Demethylation appears to occur by a DNA repair process involving the GADD45G protein.[13]

Psychiatric Disorders

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Classification and diagnosis of neuropsychiatric illnesses are symptom-based, often exhibiting similar brain activity. Furthermore, the development of psychiatric illnesses is dependent of both genetics and environmental factors, as such, predictive risk assessment of diseases such as schizophrenia has lagged behind other prevalent illnesses. Using IEGs as a marker, animal models have identified altered levels of Arc, effecting synaptic activities, and EGR1, involved in memory trace encoding, in the case of depression.[1] Similarly, other neuropsychiatric illnesses such as schizophrenia also exhibit altered IEG expresion with recent studies showing a correlation of low expression of EGR3, a transcription factor downstream of NMDARs, in patients exhibiting schizophrenia. As such, IEGs are crucial markers in evaluating neuronal activity in the context of psychiatric illness with its expression pattern shaped by environmental and genetic factors. [14]

Potential Therapeutic Application

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Human Cytomegalovirus (HCMV)

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Human Cytomegalovirus is a prevalent beta herpesvirus that remains in the latent state, going unnoticed in healthy individuals with serious consequences if the individual is immunocompromised. The virus cycles in and out of the latent state and is characterized by different gene expression regions: immediate-early (IE), early, and late.[15] Conventional anti-viral treatments such as Ganciclovir use nucleoside analogs to target the early events of the viral replication cycles, however, these approaches are prone to developing resistance. [16] Targeting IE1 and IE2 are thought to be crucial in regulating the pathogenesis of HCMV and retaining the virus in the latent state. Viral proteins derived from IE1 and IE2 regulate viral latency by controlling subsequent expression of early and late genes. [2] Silencing of IE gene expression through antisense oligonucleotides, RNA interference , and gene-targeting ribosomes have been investigated for therapeutic applications.[16][2] Alternatively, the rise of CRISPR technology allows for precise DNA editing that can knockout HCMV genes responsible for IE transcription. DNA targeting is more effective in latent infections, in which viral mRNA is absent or at a low concentration.[2] Small molecule chemical inhibitors are also being investigated that target epigenetic factors and signaling proteins involved in IE expression.

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References

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  1. ^ a b Gallo, Francisco T.; Katche, Cynthia; Morici, Juan F.; Medina, Jorge H.; Weisstaub, Noelia V. (2018-04-25). "Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc". Frontiers in Behavioral Neuroscience. 12: 79. doi:10.3389/fnbeh.2018.00079. ISSN 1662-5153. PMC 5932360. PMID 29755331.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  2. ^ a b c d Adamson, Catherine S.; Nevels, Michael M. (2020-01-16). "Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function". Viruses. 12 (1): 110. doi:10.3390/v12010110. ISSN 1999-4915. PMC 7019229. PMID 31963209.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  3. ^ Lanahan, Anthony; Worley, Paul (1998-07-01). "Immediate-Early Genes and Synaptic Function". Neurobiology of Learning and Memory. 70 (1): 37–43. doi:10.1006/nlme.1998.3836. ISSN 1074-7427.
  4. ^ Vacca, Annalaura; Itoh, Masayoshi; Kawaji, Hideya; Arner, Erik; Lassmann, Timo; Daub, Carsten O.; Carninci, Piero; Forrest, Alistair R. R.; Hayashizaki, Yoshihide; FANTOM Consortium; Aitken, Stuart (2018-08). "Conserved temporal ordering of promoter activation implicates common mechanisms governing the immediate early response across cell types and stimuli". Open Biology. 8 (8): 180011. doi:10.1098/rsob.180011. ISSN 2046-2441. PMC 6119861. PMID 30089658. {{cite journal}}: Check date values in: |date= (help)
  5. ^ a b c d Bahrami, Shahram; Drabløs, Finn (2016-09). "Gene regulation in the immediate-early response process". Advances in Biological Regulation. 62: 37–49. doi:10.1016/j.jbior.2016.05.001. ISSN 2212-4934. PMID 27220739. {{cite journal}}: Check date values in: |date= (help)
  6. ^ Xu, Chuan; Li, Qian; Efimova, Olga; Jiang, Xi; Petrova, Marina; K. Vinarskaya, Alia; Kolosov, Peter; Aseyev, Nikolay; Koshkareva, Kira; Ierusalimsky, Victor N.; Balaban, Pavel M. (2019-05-20). "Identification of Immediate Early Genes in the Nervous System of Snail Helix lucorum". eNeuro. 6 (3): ENEURO.0416–18.2019. doi:10.1523/ENEURO.0416-18.2019. ISSN 2373-2822. PMC 6584072. PMID 31053606.
  7. ^ a b Healy, Shannon; Khan, Protiti; Davie, James R. (2013-01-01). "Immediate early response genes and cell transformation". Pharmacology & Therapeutics. 137 (1): 64–77. doi:10.1016/j.pharmthera.2012.09.001. ISSN 0163-7258.
  8. ^ a b c d Minatohara, Keiichiro; Akiyoshi, Mika; Okuno, Hiroyuki (2016). "Role of Immediate-Early Genes in Synaptic Plasticity and Neuronal Ensembles Underlying the Memory Trace". Frontiers in Molecular Neuroscience. 8: 78. doi:10.3389/fnmol.2015.00078. ISSN 1662-5099.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ^ Andreasson, Katrin I.; Kaufmann, Walter E. (2002). "Role of immediate early gene expression in cortical morphogenesis and plasticity". Results and Problems in Cell Differentiation. 39: 113–137. doi:10.1007/978-3-540-46006-0_6. ISSN 0080-1844. PMID 12353466.
  10. ^ a b Gallo, Francisco T.; Katche, Cynthia; Morici, Juan F.; Medina, Jorge H.; Weisstaub, Noelia V. (2018). "Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc". Frontiers in Behavioral Neuroscience. 12: 79. doi:10.3389/fnbeh.2018.00079. ISSN 1662-5153.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ Davis, Sabrina; Bozon, Bruno; Laroche, Serge (2003-06-16). "How necessary is the activation of the immediate early gene zif268 in synaptic plasticity and learning?". Behavioural Brain Research. 142 (1): 17–30. doi:10.1016/S0166-4328(02)00421-7. ISSN 0166-4328.
  12. ^ Plath, Niels; Ohana, Ora; Dammermann, Björn; Errington, Mick L.; Schmitz, Dietmar; Gross, Christina; Mao, Xiaosong; Engelsberg, Arne; Mahlke, Claudia; Welzl, Hans; Kobalz, Ursula (2006-11). "Arc/Arg3.1 Is Essential for the Consolidation of Synaptic Plasticity and Memories". Neuron. 52 (3): 437–444. doi:10.1016/j.neuron.2006.08.024. ISSN 0896-6273. {{cite journal}}: Check date values in: |date= (help)
  13. ^ a b Li, Xiang; Marshall, Paul R.; Leighton, Laura J.; Zajaczkowski, Esmi L.; Wang, Ziqi; Madugalle, Sachithrani U.; Yin, Jiayu; Bredy, Timothy W.; Wei, Wei (2019-02-06). "The DNA Repair-Associated Protein Gadd45γ Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory". Journal of Neuroscience. 39 (6): 970–983. doi:10.1523/JNEUROSCI.2024-18.2018. ISSN 0270-6474. PMC 6363930. PMID 30545945.{{cite journal}}: CS1 maint: PMC format (link)
  14. ^ Marballi, Ketan K.; Gallitano, Amelia L. (2018). "Immediate Early Genes Anchor a Biological Pathway of Proteins Required for Memory Formation, Long-Term Depression and Risk for Schizophrenia". Frontiers in Behavioral Neuroscience. 12: 23. doi:10.3389/fnbeh.2018.00023. ISSN 1662-5153.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ Scholz, Martin; Doerr, Hans Wilhelm; Cinatl, Jindrich (2001-03). "Inhibition of cytomegalovirus immediate early gene expression: a therapeutic option?". Antiviral Research. 49 (3): 129–145. doi:10.1016/S0166-3542(01)00126-7. {{cite journal}}: Check date values in: |date= (help)
  16. ^ a b Torres, Lilith; Tang, Qiyi (2014-12). "Immediate-Early (IE) gene regulation of cytomegalovirus: IE1- and pp71-mediated viral strategies against cellular defenses". Virologica Sinica. 29 (6): 343–352. doi:10.1007/s12250-014-3532-9. ISSN 1674-0769. PMC 4654928. PMID 25501994. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
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