What is an enhancer?
Len A. Pennacchio. Enhancers are classically defined as cis-acting DNA sequences that can increase the transcription of genes. They generally function independently of orientation and at various distances from their target promoter (or promoters). Historically, the identification of enhancers has proved challenging for several reasons1.
How do Enhancers affect gene expression?
An enhancer localized in a DNA region distant from the promoter of a gene can have a very large effect on gene expression, with some genes undergoing up to 100-fold increased expression due to an activated enhancer. Enhancers are regions of the genome that are major gene-regulatory elements.
What is a protein that binds to an enhancer called?
Within this DNA sequence, protein(s) known as transcription factor(s) bind to the enhancer and increase the activity of the promoter. In genetics, an enhancer is a short (50–1500 bp) region of DNA that can be bound by proteins (activators) to increase the likelihood that transcription of a particular gene will occur.
How do enhancers increase the activity of a promoter?
Within this DNA sequence, protein(s) known as transcription factor(s) bind to the enhancer and increase the activity of the promoter. In genetics, an enhancer is a short (50-1500 bp) region of DNA that can be bound by proteins (activators) to increase the likelihood that transcription of a particular gene will occur.
What's a enhancer?
/ɪnˈhɑːn.sər/ something that is used to strengthen or improve the quality of something. Enhancer is usually used as a combining form: Music can be a mood enhancer.
What is an enhancer vs promoter?
Enhancers are short nucleotide sequences that enhance the transcription rate in the genome. Promoters are fairly large nucleotide sequences that initiate the process of transcription.
What are the function of enhancers?
Enhancer function underlies regulatory processes by which cells establish patterns of gene expression. Recent results suggest that enhancers are specified by particular chromatin marks in pluripotent cells, which may be modified later in development to alter patterns of gene expression and cell differentiation choices.
What is an example of an enhancer?
Other examples of genes with enhancers are the ß -hemoglobin gene in humans and storage proteins in soybean. One important feature of these enhancers is their tissue specificity. Storage proteins are only expressed in the seed of the soybean seed.
Is the enhancer part of the promoter?
Enhancers do not act on the promoter region itself, but are bound by activator proteins. These activator proteins interact with the mediator complex, which recruits polymerase II and the general transcription factors which then begin transcribing the genes.
How do I identify an enhancer?
Currently, enhancers can be identified through chromatin-based assays, such as ChIP-seq, which predict enhancer elements indirectly based on the enhancer's association with specific epigenomic marks, such as transcription factors or molecular tags on DNA-associated histone proteins.
What is difference between enhancers and inhibitors?
In the terms of biological chemistry the enhancers are certain chemical compounds that speeds up any biological process or any biochemical reaction. But on the other hand inhibitors are certain chemical compounds that slows down the biological process on any biochemical reaction.
How do enhancers help transcription?
Enhancers are regulatory elements that activate promoter transcription over large distances and independently of orientation (Serfling et al. 1985). While both promoters and enhancers are known to bind transcription factors (TFs), only promoters were thought to initiate transcription by RNA polymerase II (Pol II).
What are enhancers in eukaryotes?
Enhancers are positive DNA regulatory sequences controlling temporal and tissue-specific gene expression. These elements act independently of their orientation and distance relative to the promoters of target genes.
What are enhancer and promoter regions?
The promoters include specific DNA motifs where transcription factors (TFs) and their complexes can access (Hudson and Quail, 2003). On the other hand, enhancers are defined as DNA regions that amplify transcription initiation by directly interplaying with their target promoters (Blackwood and Kadonaga, 1998).
What happens if an enhancer is mutated?
b, Mutations in chromatin modifiers and TFs commonly found at enhancers often lead to neurodevelopmental and intellectual disability. This could occur via loss of DNA binding, loss of catalytic activity, or loss of protein-ribonucleotide or protein-protein interactions that mediate enhancer function.
Are enhancers upstream or downstream?
Enhancers can be located upstream of a gene, within the coding region of the gene, downstream of a gene, or thousands of nucleotides away. When a DNA -bending protein binds to the enhancer, the shape of the DNA changes, which allows interactions between the activators and transcription factors to occur.
How do enhancers differ from promoters quizlet?
A promoter is a DNA sequence near the transcription start site, which is bound by RNA polymerase during transcription initiation. Enhancers are DNA sequences that are farther away from the start site, they bind transcription factors and stimulate transcription above basal levels.
What is the difference between an enhancer and an activator?
An enhancer is a DNA sequence that promotes transcription. Each enhancer is made up of short DNA sequences called distal control elements. Activators bound to the distal control elements interact with mediator proteins and transcription factors.
What is the functional difference between enhancers and promoter proximal elements?
Furthermore, enhancer is responsible for increasing the rate of transcription while promoter is responsible for the initiation of transcription. Enhancer and promoter are the two, short DNA sequences that serve as the regulatory elements of a gene. Their main function is to regulate transcription.
How do enhancers interact with the promoter?
While an enhancer is also an important transcriptional regulatory short DNA fragments that further activate the level of transcription of its target genes by contacting close physical proximity to the promoters in the three-dimensional (3D) nuclear space [3].
What are enhancers in DNA?
Enhancers are functional DNA elements that activate the transcription of a gene from a distance, independently of their positions and orientation with respect to the transcription start site. 51,52 Enhancers contain multiple binding sites for transcription factors that increase the promoter activity to promote MYC expression. 53 In addition to traditional enhancers, the genome contains large stretches of DNA (several kilobases in size), in close linear proximity to promoters, known as super-enhancers. 52–54 Super-enhancers comprise binding sites for transcription factors (TFs), co-activators such as the Mediator complex, chromatin regulators and the RNA polymerase II complex. 53,55–58 Expression of the MYC oncogene is tightly controlled at the transcriptional level by both enhancers and super-enhancers. 50,59 Numerous recent studies have revealed that MYC contains tissue specific enhancers and super-enhancers that play an important role in tuning MYC transcription. 50,60 Super-enhancers are either generated through mutations in the enhancer regions or are acquired by DNA translocation, focal amplification, small insertion and deletion events, and transcription factor overexpression.50,59,61
What are enhancers in gene expression?
Enhancers are genomic regions of critical importance to coordinating cell-type-specific gene expression. Transcription factors associate with enhancer regions to drive specific cell lineage determination genes as well as response to stimuli.71 Currently, over 1 million enhancers are predicted across the genome, and recently, they have been found to be highly transcribed, resulting in eRNAs. 71–74 eRNAs may be the result of pervasive transcription initiating from the enhancer and may be rapidly degraded; however, eRNAs have also been demonstrated to functionally alter histone methylation and recruitment of transcriptional machinery to enhancer regions and may also alter chromatin looping surrounding enhancers resulting in aberrant gene expression programs.
What are core histone modifications?
Core histone modifications mark the activity of enhancers in specific cell types and tissues. Active enhancers are marked by mono-methylation at lysine 4 and acetylation at lysine 27 of histone H3 (H3K4me1 and H3K27ac), while poised enhancers are decorated with H3K4me1 and tri-methylation at lysine 27 of histone H3 (H3K27me3). Bioinformatics analyses of ChIP-seq studies have led to the identification of groups of closely spaced enhancers variably named transcriptional initiation platforms (TIPs), stretch enhancers, or more commonly super-enhancers. Super-enhancers are characterized by the enrichment of master transcription factors, a high level of occupancy of the Mediator complex, and they are comprised of ∼ 10 kb genomic regions on average. Super-enhancers are found to be associated with key cell identity genes but not housekeeping genes. Super-enhancers have been identified near oncogenes such as c-Myc and TAL1 in cancer cells but not normal cells, suggesting that tumors acquire super-enhancers at oncogenes during pathogenesis. Super-enhancers overlap with many previously characterized LCRs, indicating that it is possible that these extended regulatory regions are clusters of regular enhancers. Do individual enhancers within a super-enhancer region have synergistic effects on nearby genes? To answer this question, the α-globin regulatory region, a typical super-enhancer, has been carefully analyzed. Individual deletion of the five enhancers in the α-globin super-enhancer demonstrated that the enhancer elements act in an additive manner. None of the five enhancers were solely responsible for the activation of the α-globin gene, and the effect of compound deletion was similar to that of the additive results of single-enhancer deletions. This suggests that individual enhancers in one super-enhancer region may work independently from each other. However, in other cases, enhancers in a cluster may work as “shadow enhancers,” a term used to describe the discovery of seemingly functionally redundant enhancers in Drosophila for genes that already have known enhancers. In mammals, two “shadow enhancer” like regulatory elements are present in the HoxA gene cluster, with the removal of either enhancer having little effect whereas deletion of the two enhancers significantly impairs HoxA gene activation. It is likely that the “shadow enhancer” mechanism is frequently utilized to guarantee the well-regulated expression of important genes during development.
What are enhancers in the human globin gene?
Enhancers such as those in the locus control region (LCR) of the human β globin gene are able to drive the expression of genes across a long distance. Located 60 kilobases (kb) upstream of the human β globin gene, the LCR of β globin contains five DNase I hypersensitive sites (HS), and controls the expression of the five genes in the β globin locus during embryonic development. Mutations in the LCR can lead to thalassemia, a disease characterized by insufficient hemoglobin function. In general, the temporal and spatial regulation of tissue specific genes is driven by enhancers. For example, the ordered expression of the homeotic (Hox) genes are controlled through a cohort of enhancers located upstream and downstream of their gene clusters during development. The orientation of the enhancers does not seem to be critical for transcription activation but their localization in particular local chromatin environments can regulate their activity.
How do enhancers and silencers regulate transcription?
Enhancer and silencer elements regulate transcription through the binding of a multitude of TFs that activate or repress transcription. These transcription factor-binding elements influence transcription irrespective of location; they may lie proximal to the core promoter or several hundreds of base pairs from the TSS, or even on other chromosomes. Given the limited number of transcription factors compared with the number of genes under transcriptional regulation, and the repetitious use of the same transcriptional machinery, it is the enhancer and silencing motifs found proximally and distally that provide much of the temporal and spatial regulation of transcription. Through the binding of transcription factors, enhancer elements direct which genes are to be transcribed, when transcription takes place, for how long, and at what level of intensity.
What are enhancer regions?
Enhancer regions contain binding motifs for sequence-specific TFs [114] and regulate the expression of target genes through looping interaction with the gene promoters [8,66].
Where are enhancers found in the human and mouse genome?
Enhancers 3’ of the constant gene segments have been found in lambda loci in mouse and human. Both the murine and human elements are illustrated in Figure 6.2 because the human element has been studied in some detail recently ( Asenbauer, Combriato et al., 1999). Most protein binding sites in these enhancers are also found in other Ig enhancers, but a role for Mef proteins appears to be unique to the lambda enhancers ( Satyaraj and Storb, 1998 ). A role for PU.1/IRF-4 in the murine lambda enhancer was evident in early studies ( Pongubala, Nagulapalli et al., 1992; Eisenbeis, Singh et al., 1993) and provided a paradigm for understanding the activity of PU.1, in conjunction with other proteins, in many Ig enhancers.
What is an enhancer?
Len A. Pennacchio. Enhancers are classically defined as cis -acting DNA sequences that can increase the transcription of genes. They generally function independently of orientation and at various distances from their target promoter (or promoters).
How many enhancers are there in the human genome?
It is estimated that the human genome contains hundreds of thousands of enhancers, so understanding these gene-regulatory elements is a crucial goal.
What enhancers are required for Pol II elongation?
Enhancer looping also appears to have a role in Pol II elongation. The LCR and the β-globin looping factor LIM-domain-binding 1 (LDB1) are needed for proper release of Pol II from pausing within the β-globin gene30,31. Most recently, the elongation factor ELL3 was found to occupy enhancers in ESCs32. The association of ELL3 with the enhancers was required for proper Pol II occupancy at developmentally regulated genes. Both cohesin and Mediator were found to be associated with many ELL3-occupied enhancers and cohesin mediated long-range interactions of an ELL3-occupied enhancer in the homeobox cluster A (HOXA) locus. Together, these studies show that enhancers can influence both Pol II initiation and elongation through direct participation of transcription machinery components in looping.
How do loops form between enhancers and promoters?
The first is the cross-linking, by formaldehyde, and subsequent ligation together of enhancer and promoter DNA sequences as detected in chromosome conformation capture (3C)-type methods. The second is the visualization, by fluorescence in situhybridization (FISH), of the spatial proximity of enhancer and promoter regions in the cell nucleus. In some cases, both of these assays do indeed support looping mechanisms that bring distant cis-regulatory elements into very close (<200 nm) proximity of their target genes in a tissue-restricted manner.
Why are enhancers so difficult to identify?
First, enhancers are scattered across the 98% of the human genome that does not encode proteins, resulting in a large search space (billions of base pairs of DNA).
Which cis-regulatory element is most widely assayed?
Finally, it is important to recall that enhancers are only the most widely assayed of the cis -regulatory elements. Repression of gene expression and insulator-mediated partitioning of the genome into gene regulatory domains are probably also important contributors to gene regulation and its evolution.
Can enhancers be identified from DNA sequence alone?
Thus, enhancers cannot be identified computationally from DNA sequence alone with high confidence. Finally, the activity of enhancers can be restricted to a particular tissue or cell type, a time point in life, or to specific physiological, pathological or environmental conditions.
Overview
In genetics, an enhancer is a short (50–1500 bp) region of DNA that can be bound by proteins (activators) to increase the likelihood that transcription of a particular gene will occur. These proteins are usually referred to as transcription factors. Enhancers are cis-acting. They can be located up to 1 Mbp (1,000,000 bp) away from the gene, upstream or downstream from the start site. There are hundred…
Locations
In eukaryotic cells the structure of the chromatin complex of DNA is folded in a way that functionally mimics the supercoiled state characteristic of prokaryotic DNA, so although the enhancer DNA may be far from the gene in a linear way, it is spatially close to the promoter and gene. This allows it to interact with the general transcription factors and RNA polymerase II. The same mechanism hol…
Theories
As of 2005 , there are two different theories on the information processing that occurs on enhancers:
• Enhanceosomes – rely on highly cooperative, coordinated action and can be disabled by single point mutations that move or remove the binding sites of individual proteins.
• Flexible billboards – less integrative, multiple proteins independently regulate gene expression and their sum is read i…
Examples in the human genome
HACNS1 (also known as CENTG2 and located in the Human Accelerated Region 2) is a gene enhancer "that may have contributed to the evolution of the uniquely opposable human thumb, and possibly also modifications in the ankle or foot that allow humans to walk on two legs". Evidence to date shows that of the 110,000 gene enhancer sequences identified in the human genome, HACNS1 has undergone the most change during the evolution of humans following the split with …
In developmental biology
The development, differentiation and growth of cells and tissues require precisely regulated patterns of gene expression. Enhancers work as cis-regulatory elements to mediate both spatial and temporal control of development by turning on transcription in specific cells and/or repressing it in other cells. Thus, the particular combination of transcription factors and other DNA-binding proteins in a developing tissue controls which genes will be expressed in that tissue. Enhancers …
Evolution of developmental mechanisms
One theme of research in evolutionary developmental biology ("evo-devo") is investigating the role of enhancers and other cis-regulatory elements in producing morphological changes via developmental differences between species.
Recent work has investigated the role of enhancers in morphological changes in threespine stickleback fish. Sticklebacks exist in both marine and freshwater environments, but stickleback…
See also
• Shadow enhancers
External links
• Enhancer+Elements,Genetic at the US National Library of Medicine Medical Subject Headings (MeSH)
• TFSEARCH
• JASPAR
• ReMap