Immediate early gene

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Immediate early genes (IEGs) are genes which 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.

Contents

In their role as "gateways to genomic response", many IEG products are natural transcription factors or other DNA-binding proteins. However, other important classes of IEG products include secreted proteins, cytoskeletal proteins, and receptor subunits. Neuronal IEGs are used prevalently as a marker to track brain activities 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]

Types

The earliest identified and best characterized IEGs 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. [3] Arc/Arg3.1, Zif268 and Homer are IEGs that regulate synaptic strength in neurons. [4]

Regulation

Expression of IEGs occurs in response to internal and external cell signals, occurring rapidly without the need to synthesize new transcription factors. [5] The genetic sequences of IEGs are generally shorter in length (~19kb) and exhibit an enrichment of specific transcription factor binding sites, offering redundancy in transcription initiation. [6] Translation of IEG mRNA into proteins occurs regardless of protein synthesis inhibitors which disrupts the process of protein production. [7] Rapid expression of IEGs is also attributed to the accessibility of its promotor sequence through histone acetylation that is consistent pre- and post-expression. [6] Downregulation of mRNA transcription occurs through redundant 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. [6]

Function

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. [8] There are many signaling pathways leading to the activation of IEGs, many of which (MAPK/ERK, PI3K, etc.) are studied in the context of cancer. [6] As such, many IEGs function as transcription factors regulating expression of downstream genes or are proto-oncogenes associated with altered cell growth. [8]

IEGs in neurobiological research

Expression of IEGs is involved in neuronal activity and specifically memory formation, neuropsychiatric diseases, and behavioral activities. [9] 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. [10] These changes are theorized to be the means in which memory is stored in the brain as outline in the concept 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 [11]

Memory formation

Expression of IEG c-Fos in neurons responding to stimulation with potassium treatment CFos-expression-in-stimulated-neurons.jpg
Expression of IEG c-Fos in neurons responding to stimulation with potassium treatment

Some IEGs such as ZNF268 and Arc have been implicated in learning and memory and long-term potentiation. [12] [13]

A wide range of neuronal stimulation have been shown to induce IEG expression ranging from sensory and behavioral to drug-induced convulsions. [9] 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. [11] 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. [9] 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. [9] 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. [14] 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. [14]

Psychiatric disorders

IEGs are used as markers in animal models of depression. Affected mice have altered levels of Arc,affecting synaptic activity, and EGR1, involved in memory trace encoding. [1] Other neuropsychiatric illnesses such as schizophrenia also exhibit altered IEG expression, with recent studies showing a correlation of low expression of EGR3 , a transcription factor downstream of NMDARs, in patients exhibiting schizophrenia. [15] 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. [15]

Potential therapeutic applications

Human cytomegalovirus

Human cytomegalovirus (HCMV) is a prevalent beta herpesvirus that remains in the latent state, going unnoticed in healthy individuals but having 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. [16] 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. [17] 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. [2] [17] 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. [2]

Related Research Articles

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. Some segments of DNA are transcribed into RNA molecules that can encode proteins, called messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

<span class="mw-page-title-main">Fear conditioning</span> Behavioral paradigm in which organisms learn to predict aversive events

Pavlovian fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events. It is a form of learning in which an aversive stimulus is associated with a particular neutral context or neutral stimulus, resulting in the expression of fear responses to the originally neutral stimulus or context. This can be done by pairing the neutral stimulus with an aversive stimulus. Eventually, the neutral stimulus alone can elicit the state of fear. In the vocabulary of classical conditioning, the neutral stimulus or context is the "conditional stimulus" (CS), the aversive stimulus is the "unconditional stimulus" (US), and the fear is the "conditional response" (CR).

<span class="mw-page-title-main">Brain-derived neurotrophic factor</span> Protein found in humans

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

<span class="mw-page-title-main">CREB</span> Class of proteins

CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.

<span class="mw-page-title-main">NF-κB</span> Family of transcription factor protein complexes

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.

<span class="mw-page-title-main">Silencer (genetics)</span> Type of DNA sequence

In genetics, a silencer is a DNA sequence capable of binding transcription regulation factors, called repressors. DNA contains genes and provides the template to produce messenger RNA (mRNA). That mRNA is then translated into proteins. When a repressor protein binds to the silencer region of DNA, RNA polymerase is prevented from transcribing the DNA sequence into RNA. With transcription blocked, the translation of RNA into proteins is impossible. Thus, silencers prevent genes from being expressed as proteins.

<span class="mw-page-title-main">HHV Infected Cell Polypeptide 0</span> Protein

Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is a protein, encoded by the DNA of herpes viruses. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the host cell; this stage is known as the immediate-early or α ("alpha") phase of viral gene expression. During these early stages of infection, ICP0 protein is synthesized and transported to the nucleus of the infected host cell. Here, ICP0 promotes transcription from viral genes, disrupts structures in the nucleus known as nuclear dots or promyelocytic leukemia (PML) nuclear bodies, and alters the expression of host and viral genes in combination with a neuron specific protein. At later stages of cellular infection, ICP0 relocates to the cell cytoplasm to be incorporated into new virion particles.

<span class="mw-page-title-main">Protein kinase R</span> Human protein and coding gene

Protein kinase RNA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by the EIF2AK2 gene on chromosome 2. PKR is a serine/tyrosine kinase that is 551 amino acids long.

<span class="mw-page-title-main">Protein c-Fos</span> Mammalian protein found in Homo sapiens

Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the FOS gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV. It is a part of a bigger Fos family of transcription factors which includes c-Fos, FosB, Fra-1 and Fra-2. It has been mapped to chromosome region 14q21→q31. c-Fos encodes a 62 kDa protein, which forms heterodimer with c-jun, resulting in the formation of AP-1 complex which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression. It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers.

Activity-dependent plasticity is a form of functional and structural neuroplasticity that arises from the use of cognitive functions and personal experience; hence, it is the biological basis for learning and the formation of new memories. Activity-dependent plasticity is a form of neuroplasticity that arises from intrinsic or endogenous activity, as opposed to forms of neuroplasticity that arise from extrinsic or exogenous factors, such as electrical brain stimulation- or drug-induced neuroplasticity. The brain's ability to remodel itself forms the basis of the brain's capacity to retain memories, improve motor function, and enhance comprehension and speech amongst other things. It is this trait to retain and form memories that is associated with neural plasticity and therefore many of the functions individuals perform on a daily basis. This plasticity occurs as a result of changes in gene expression which are triggered by signaling cascades that are activated by various signaling molecules during increased neuronal activity.

<span class="mw-page-title-main">Activity-regulated cytoskeleton-associated protein</span> Protein-coding gene in the species Homo sapiens

Activity-regulated cytoskeleton-associated protein is a plasticity protein that in humans is encoded by the ARC gene. The gene is believed to derive from a retrotransposon. The protein is found in the neurons of tetrapods and other animals where it can form virus-like capsids that transport RNA between neurons.

The cellular transcription factor CREB helps learning and the stabilization and retrieval of fear-based, long-term memories. This is done mainly through its expression in the hippocampus and the amygdala. Studies supporting the role of CREB in cognition include those that knock out the gene, reduce its expression, or overexpress it.

miR-132 Non-coding RNA molecule

In molecular biology miR-132 microRNA is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms, generally reducing protein levels through the cleavage of mRNAs or the repression of their translation. Several targets for miR-132 have been described, including mediators of neurological development, synaptic transmission, inflammation and angiogenesis.

While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription responsible for memory formation and maintenance. Epigenetic gene regulation often involves the physical marking of DNA or associated proteins to cause or allow long-lasting changes in gene activity. Epigenetic mechanisms such as DNA methylation and histone modifications have been shown to play an important role in learning and memory.

Enhancer RNAs (eRNAs) represent a class of relatively long non-coding RNA molecules transcribed from the DNA sequence of enhancer regions. They were first detected in 2010 through the use of genome-wide techniques such as RNA-seq and ChIP-seq. eRNAs can be subdivided into two main classes: 1D eRNAs and 2D eRNAs, which differ primarily in terms of their size, polyadenylation state, and transcriptional directionality. The expression of a given eRNA correlates with the activity of its corresponding enhancer in target genes. Increasing evidence suggests that eRNAs actively play a role in transcriptional regulation in cis and in trans, and while their mechanisms of action remain unclear, a few models have been proposed.

Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.

Epigenetics of depression is the study of how epigenetics contribute to depression.

Neuroepigenetics is the study of how epigenetic changes to genes affect the nervous system. These changes may effect underlying conditions such as addiction, cognition, and neurological development.

References

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  4. ↑ Guzowski JF, Setlow B, Wagner EK, McGaugh JL (2001-07-15). "Experience-Dependent Gene Expression in the Rat Hippocampus after Spatial Learning: A Comparison of the Immediate-Early Genes Arc, c- fos, and zif268". The Journal of Neuroscience. 21 (14): 5089–5098. doi: 10.1523/JNEUROSCI.21-14-05089.2001 . ISSN   0270-6474. PMC   6762831 . PMID   11438584.
  5. ↑ Vacca A, Itoh M, Kawaji H, Arner E, Lassmann T, Daub CO, et al. (August 2018). "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. PMC   6119861 . PMID   30089658.
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  8. 1 2 Healy S, Khan P, Davie JR (January 2013). "Immediate early response genes and cell transformation". Pharmacology & Therapeutics. 137 (1): 64–77. doi:10.1016/j.pharmthera.2012.09.001. PMID   22983151.
  9. 1 2 3 4 Minatohara K, Akiyoshi M, Okuno H (2016-01-05). "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 . PMC   4700275 . PMID   26778955.
  10. ↑ Andreasson KI, Kaufmann WE (2002). "Role of Immediate Early Gene Expression in Cortical Morphogenesis and Plasticity". Cortical Development. Results and Problems in Cell Differentiation. Vol. 39. pp. 113–37. doi:10.1007/978-3-540-46006-0_6. ISBN   978-3-642-53665-6. PMID   12353466.
  11. 1 2 Gallo FT, Katche C, Morici JF, Medina JH, Weisstaub NV (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 . PMC   5932360 . PMID   29755331.
  12. ↑ Davis S, Bozon B, Laroche S (June 2003). "How necessary is the activation of the immediate early gene zif268 in synaptic plasticity and learning?". Behavioural Brain Research. 142 (1–2): 17–30. doi:10.1016/S0166-4328(02)00421-7. PMID   12798262. S2CID   41734654.
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  15. 1 2 Marballi KK, Gallitano AL (2018-02-19). "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 . PMC   5827560 . PMID   29520222.
  16. ↑ Scholz M, Doerr HW, Cinatl J (March 2001). "Inhibition of cytomegalovirus immediate early gene expression: a therapeutic option?". Antiviral Research. 49 (3): 129–45. doi:10.1016/s0166-3542(01)00126-7. PMID   11428240.
  17. 1 2 Torres L, Tang Q (December 2014). "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. PMC   4654928 . PMID   25501994.
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