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Immediate early genes (IEGs) are
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s 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. In their role as "gateways to genomic response", many IEG products are natural
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s or other
DNA-binding protein DNA-binding proteins are proteins that have DNA-binding domains and thus have a specific or general affinity for single- or double-stranded DNA. Sequence-specific DNA-binding proteins generally interact with the major groove of B-DNA, becaus ...
s. 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. IEGs are also of interest as a therapeutic target for treatment of
human cytomegalovirus ''Human betaherpesvirus 5'', also called human cytomegalovirus (HCMV), is species of virus in the genus '' Cytomegalovirus'', which in turn is a member of the viral family known as '' Herpesviridae'' or herpesviruses. It is also commonly cal ...
.


Types

The earliest identified and best characterized IEGs include ''
c-fos 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 (Finkel–Biskis–Jink ...
'', ''
c-myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes re ...
'' and ''
c-jun Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only la ...
'', genes that were found to be homologous to
retroviral A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
s. 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.


Regulation

Expression of IEGs occurs in response to internal and external cell signals, occurring rapidly without the need to synthesis new
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
. 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. Translation of IEG mRNA into proteins occurs regardless of protein synthesis inhibitors which disrupts the process of protein production. Rapid expression of IEGs are also attributed to the accessibility of its promotor sequence through histone acetylation that is consistent pre- and post-expression. Downregulation of mRNA transcription occurs through redundant targeting of the
3' UTR In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...
region by
microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. mi ...
s, resulting in translational repression and degradation. The expression of IEG protein is often transient due to rapid mRNA downregulation and increased
proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
of translated products.


Function

Activation of gene transcription is a complex system of signal cascades and recruitment of necessary components such as
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens th ...
and
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
. 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. There are many singaling pathways leading to the activation of IEGs, many of which ( MAPK/ERK,
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
, etc.) are studied in the context of cancer. As such, many IEGs function as transcription factors regulating expression of downstream genes or are proto-
oncogenes An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
associated with altered cell growth.


Clinical significance

IEGs expression is involved in neuronal activity and specifically memory formation, neuropsychiatric diseases, and behavioral activities. 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. 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 Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...
,
Panic disorder Panic disorder is a mental and behavioral disorder, specifically an anxiety disorder characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, short ...
,
Post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats o ...


Memory formation

Some IEGs such as '' ZNF268'' and Arc have been implicated in
learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, values, attitudes, and preferences. The ability to learn is possessed by humans, animals, and some machines; there is also evidence for some kind of lea ...
and
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remember ...
and
long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
. A wide range of neuronal stimulation have been shown to induce IEG expression ranging from sensory and behavioral to drug-induced convulsions. 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. 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. 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 A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, a ...
of '' Arc'' showing adverse affects on the formation of long-term memory. These findings offer insight into the molecular mechanism and functional changes brought about by IEG expression, expanding the theory of memory trace.
Memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remember ...
consolidation during a
learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, values, attitudes, and preferences. The ability to learn is possessed by humans, animals, and some machines; there is also evidence for some kind of lea ...
experience depends on the rapid expression of a set of IEGs in
brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
.; In general,
expression of genes Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. Th ...
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 Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen at ...
of 5-methylcytosine to form the normal base
cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ( ...
can induce rapid gene expression. Demethylation appears to occur by a
DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
process involving the GADD45G protein.


Psychiatric disorders

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 Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...
has lagged behind other prevalent illnesses. Using IEGs as a marker, animal models have identified altered levels of '' Arc,''effecting synaptic activities, and ''
EGR1 EGR-1 (Early growth response protein 1) also known as ZNF268 (zinc finger protein 268) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the ''EGR1'' gene. EGR-1 is a mammalian transcription factor. It wa ...
,'' involved in memory trace encoding, in the case of depression. Similarly, 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. 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.


Potential therapeutic applications


Human Cytomegalovirus (HCMV)

Human Cytomegalovirus ''Human betaherpesvirus 5'', also called human cytomegalovirus (HCMV), is species of virus in the genus '' Cytomegalovirus'', which in turn is a member of the viral family known as '' Herpesviridae'' or herpesviruses. It is also commonly cal ...
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. Conventional anti-viral treatments such as
Ganciclovir Ganciclovir, sold under the brand name Cytovene among others, is an antiviral medication used to treat cytomegalovirus (CMV) infections. Ganciclovir was patented in 1980 and approved for medical use in 1988. Medical use Ganciclovir is indicated ...
use nucleoside analogs to target the early events of the viral replication cycles, however, these approaches are prone to developing resistance. 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. Silencing of IE gene expression through antisense oligonucleotides,
RNA interference RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by ...
, and gene-targeting ribosomes have been investigated for therapeutic applications. Alternatively, the rise of
CRISPR CRISPR () (an acronym for clustered regularly interspaced short palindromic repeats) is a family of DNA sequences found in the genomes of prokaryotic organisms such as bacteria and archaea. These sequences are derived from DNA fragments of bact ...
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. Small molecule chemical inhibitors are also being investigated that target epigenetic factors and signaling proteins involved in IE expression.


References


External links


Activation of Immediate Early Genes by Drugs of Abuse
a monograph published by the
National Institute on Drug Abuse The National Institute on Drug Abuse (NIDA) is a United States federal government research institute whose mission is to "advance science on the causes and consequences of drug use and addiction and to apply that knowledge to improve individual a ...
* *{{MeshName, Immediate-Early+Proteins Genes