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.
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. IEGs are also of interest as a therapeutic target for treatment of human cytomegalovirus.
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. Arc/Arg3.1, Zif268 and Homer are IEGs that regulate synaptic strength in neurons.
Regulation
Expression of IEGs occurs in response to internal and external cell signals, occurring rapidly without the need to synthesize new transcription factors. 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. Translation of IEG mRNA into proteins occurs regardless of protein synthesis inhibitors which disrupts the process of protein production. Rapid expression of IEGs is also attributed to the accessibility of its promotor sequence through histone acetylation that is consistent pre- and post-expression. 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. 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, Panic disorder, Post-traumatic stress disorder
Memory formation
thumb|389x389px|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.
A wide range of neuronal stimulation have been shown to induce IEG expression ranging from sensory and behavioral to drug-induced convulsions. 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. 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. 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. 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.