An enhanceosome is a protein complex that assembles at an enhancer region on DNA and helps to regulate the expression of a target gene. [1]
An enhanceosome is a protein complex that assembles at an enhancer region on DNA and helps to regulate the expression of a target gene. [1]
Enhancers are bound by transcription activator proteins and transcriptional regulation is typically controlled by more than one activator. Enhanceosomes are formed in special cases when these activators cooperatively bind together along the enhancer sequence to create a distinct three-dimensional structure. Each enhanceosome is unique towards its specific enhancer. This assembly is facilitated by energetically favorable protein: protein and protein: DNA interactions. Therefore, all the necessary activators need to be present for the enhanceosome to be formed and able to function. [1]
Once the enhanceosome has been formed, it recruits coactivators and general transcription factors to the promoter region of the target gene to begin transcription. [2] The effectiveness of this is dependent on DNA conformation. As a result, the enhanceosome also recruits non histone architectural transcription factors, called high-mobility group (HMG) proteins, which are responsible for regulating chromatin structure. [3] These factors do not bind to the enhancer, but instead are used to restructure the DNA to ensure that the genes can be accessed by the transcription factors.
Most enhanceosomes have been discovered pertaining to genes requiring tight regulation, like those associated with the cells defense system. [4] Using more than one kind of transcriptional activator protein could help to ensure that a gene is not transcribed prematurely. Furthermore, the use of multiple factors enables gene regulation through a combination of cellular stimuli that function through multiple signaling cascades.
The best known example of the enhanceosome acts on the human interferon-beta gene, which is upregulated in cells that are infected by viruses. [5] Three activator proteins—NF-κB, an interferon activator protein such as IRF-3, and the ATF-2/c-Jun complex—cooperatively bind to the upstream enhancer region upon viral infection. The interaction is mediated by a fourth protein HMG-I, which assists in stabilizing the complex by promoting inter-protein interactions. The assembled enhanceosome recruits transcriptional machinery such as RNA polymerase to the promoter region to initiate gene expression. [1] [5] [6]
Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.
In molecular biology, a transcription factor (TF) 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 function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the desired cells at the right time and in the right amount throughout the life of the cell and the organism. Groups of TFs function in a coordinated fashion to direct cell division, cell growth, and cell death throughout life; cell migration and organization during embryonic development; and intermittently in response to signals from outside the cell, such as a hormone. There are approximately 1600 TFs in the human genome. Transcription factors are members of the proteome as well as regulome.
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.
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.
Transcription factor Sp1, also known as specificity protein 1* is a protein that in humans is encoded by the SP1 gene.
A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.
An insulator is a type of cis-regulatory element known as a long-range regulatory element. Found in multicellular eukaryotes and working over distances from the promoter element of the target gene, an insulator is typically 300 bp to 2000 bp in length. Insulators contain clustered binding sites for sequence specific DNA-binding proteins and mediate intra- and inter-chromosomal interactions.
The p300-CBP coactivator family in humans is composed of two closely related transcriptional co-activating proteins :
In genetics and cell biology, repression is a mechanism often used to decrease or inhibit the expression of a gene. Removal of repression is called derepression. This mechanism may occur at different stages in the expression of a gene, with the result of increasing the overall RNA or protein products. Dysregulation of derepression mechanisms can result in altered gene expression patterns, which may lead to negative phenotypic consequences such as disease.
Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene. CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination and regulation of chromatin architecture.
Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.
An E-box is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG, with a palindromic canonical sequence of CACGTG, is recognized and bound by transcription factors to initiate gene transcription. Once the transcription factors bind to the promoters through the E-box, other enzymes can bind to the promoter and facilitate transcription from DNA to mRNA.
High-mobility group protein HMG-I/HMG-Y is a protein that in humans is encoded by the HMGA1 gene.
Interferon regulatory factor 1 is a protein that in humans is encoded by the IRF1 gene.
Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene.
Cellular memory modules are a form of epigenetic inheritance that allow cells to maintain their original identity after a series of cell divisions and developmental processes. Cellular memory modules implement these preserved characteristics into transferred environments through transcriptional memory. Cellular memory modules are primarily found in Drosophila.
An upstream activating sequence or upstream activation sequence (UAS) is a cis-acting regulatory sequence found in yeast like Saccharomyces cerevisiae. It is distinct from the promoter and increases the expression of a neighbouring gene. Due to its essential role in activating transcription, the upstream activating sequence is often considered to be analogous to the function of the enhancer in multicellular eukaryotes. Upstream activation sequences are a crucial part of induction, enhancing the expression of the protein of interest through increased transcriptional activity. The upstream activation sequence is found adjacently upstream to a minimal promoter and serves as a binding site for transactivators. If the transcriptional transactivator does not bind to the UAS in the proper orientation then transcription cannot begin. To further understand the function of an upstream activation sequence, it is beneficial to see its role in the cascade of events that lead to transcription activation. The pathway begins when activators bind to their target at the UAS recruiting a mediator. A TATA-binding protein subunit of a transcription factor then binds to the TATA box, recruiting additional transcription factors. The mediator then recruits RNA polymerase II to the pre-initiation complex. Once initiated, RNA polymerase II is released from the complex and transcription begins.
Pioneer factors are transcription factors that can directly bind condensed chromatin. They can have positive and negative effects on transcription and are important in recruiting other transcription factors and histone modification enzymes as well as controlling DNA methylation. They were first discovered in 2002 as factors capable of binding to target sites on nucleosomal DNA in compacted chromatin and endowing competency for gene activity during hepatogenesis. Pioneer factors are involved in initiating cell differentiation and activation of cell-specific genes. This property is observed in histone fold-domain containing transcription factors and other transcription factors that use zinc finger(s) for DNA binding.
Robert E. Kingston is an American biochemist and geneticist who studies the functional and regulatory role nucleosomes play in gene expression, specifically during early development. After receiving his PhD (1981) and completing post-doctoral research, Kingston became an assistant professor at Massachusetts General Hospital (1985), where he started a research laboratory focused on understanding chromatin's structure with regards to transcriptional regulation. As a Harvard graduate himself, Kingston has served his alma mater through his leadership.