Enhancer (genetics)
In
The first discovery of a eukaryotic enhancer was in the immunoglobulin heavy chain gene in 1983.[5][6][7] This enhancer, located in the large intron, provided an explanation for the transcriptional activation of rearranged Vh gene promoters while unrearranged Vh promoters remained inactive.[8] Lately, enhancers have been shown to be involved in certain medical conditions, for example, myelosuppression.[9] Since 2022, scientists have used artificial intelligence to design synthetic enhancers and applied them in animal systems, first in a cell line,[10] and one year later also in vivo.[11][12]
Locations
In
An enhancer may be located
Enhancers are bound by
Role in gene expression
Gene expression in mammals is regulated by many cis-regulatory elements, including core promoters and promoter-proximal elements that are located near the transcription start sites of genes. Core promoters are sufficient to direct transcription
initiation, but generally have low basal activity.
Enhancers are regions of the genome that are major gene-regulatory elements. Enhancers control cell-type-specific gene expression programs, most often by looping through long distances to come in physical proximity with the promoters of their target genes.[28] While there are hundreds of thousands of enhancer DNA regions,[2] for a particular type of tissue only specific enhancers are brought into proximity with the promoters that they regulate. In a study of brain cortical neurons, 24,937 loops were found, bringing enhancers to their target promoters.[27] Multiple enhancers, each often at tens or hundreds of thousands of nucleotides distant from their target genes, loop to their target gene promoters and can coordinate with each other to control the expression of their common target gene.[28]
The schematic illustration in this section shows an enhancer looping around to come into close physical proximity with the promoter of a target gene. The loop is stabilized by a dimer of a connector protein (e.g. dimer of CTCF or YY1), with one member of the dimer anchored to its binding motif on the enhancer and the other member anchored to its binding motif on the promoter (represented by the red zigzags in the illustration).[29] Several cell function specific transcription factors (there are about 1,600 transcription factors in a human cell[30]) generally bind to specific motifs on an enhancer[31] and a small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern level of transcription of the target gene. Mediator (a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (pol II) enzyme bound to the promoter.[32]
Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two Enhancer RNAs (eRNAs) as illustrated in the Figure.[33] Like mRNAs, these eRNAs are usually protected by their 5′ cap.[34] An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the transcription factor may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of transcription factor bound to enhancer in the illustration).[35] An activated enhancer begins transcription of its RNA before activating transcription of messenger RNA from its target gene.[36]
Theories
As of 2005[update], there are two different theories on the information processing that occurs on enhancers:[37]
- point mutationsthat move or remove the binding sites of individual proteins.
- Flexible billboards – less integrative, multiple proteins independently regulate gene expression and their sum is read in by the basal transcriptional machinery.
Examples in the human genome
HACNS1
HACNS1 (also known as
GADD45G
An enhancer near the gene GADD45g has been described that may regulate brain growth in chimpanzees and other mammals, but not in humans.[38] The GADD45G regulator in mice and chimps is active in regions of the brain where cells that form the cortex, ventral forebrain, and thalamus are located and may suppress further neurogenesis. Loss of the GADD45G enhancer in humans may contribute to an increase of certain neuronal populations and to forebrain expansion in humans.[citation needed]
In developmental biology
The development, differentiation and growth of cells and tissues require precisely regulated patterns of
Identification and characterization
Traditionally, enhancers were identified by
The development of genomic and epigenomic technologies, however, has dramatically changed the outlook for
In segmentation of insects
The enhancers determining early
In vertebrate patterning
Establishing body axes is a critical step in animal development. During mouse embryonic development,
Establishing three
Multiple enhancers promote developmental robustness
Some genes involved in critical developmental processes contain multiple enhancers of overlapping function. Secondary enhancers, or "shadow enhancers", may be found many kilobases away from the primary enhancer ("primary" usually refers to the first enhancer discovered, which is often closer to the gene it regulates). On its own, each enhancer drives nearly identical patterns of gene expression. Are the two enhancers truly redundant? Recent work has shown that multiple enhancers allow fruit flies to survive environmental perturbations, such as an increase in temperature. When raised at an elevated temperature, a single enhancer sometimes fails to drive the complete pattern of expression, whereas the presence of both enhancers permits normal gene expression.[50]
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.[citation needed]
Stickleback Pitx1
Recent work has investigated the role of enhancers in morphological changes in threespine
In Drosophila wing pattern evolution
Pigmentation patterns provide one of the most striking and easily scored differences between different species of animals. Pigmentation of the Drosophila wing has proven to be a particularly amenable system for studying the development of complex pigmentation phenotypes. The Drosophila guttifera wing has 12 dark pigmentation spots and 4 lighter gray intervein patches. Pigment spots arise from expression of the yellow gene, whose product produces black melanin. Recent work has shown that two enhancers in the yellow gene produce gene expression in precisely this pattern – the vein spot enhancer drives reporter gene expression in the 12 spots, and the intervein shade enhancer drives reporter expression in the 4 distinct patches. These two enhancers are responsive to the Wnt signaling pathway, which is activated by wingless expression at all of the pigmented locations. Thus, in the evolution of the complex pigmentation phenotype, the yellow pigment gene evolved enhancers responsive to the wingless signal and wingless expression evolved at new locations to produce novel wing patterns.[52]
In inflammation and cancer
Each cell typically contains several hundred of a special class of enhancers that stretch over many kilobases long DNA sequences, called "
Designing enhancers in synthetic biology
Synthetic regulatory elements such as enhancers promise to be a powerful tool to direct gene products to particular cell types in order to treat disease by activating beneficial genes or by halting aberrant cell states.
Since 2022, artificial intelligence and transfer learning strategies have led to a better understanding of the features of regulatory DNA sequences, the prediction, and the design of synthetic enhancers. [61][62]
Building on work in cell culture,[63] synthetic enhancers were successfully applied to entire living organisms in 2023. Using deep neural networks, scientists simulated the evolution of DNA sequences to analyze the emergence of features that underly enhancer function. This allowed the design and production of a range of functioning synthetic enhancers for different cell types of the fruit fly brain.[64] A second approach trained artificial intelligence models on single-cell DNA accessibility data and transferred the learned models towards the prediction of enhancers for selected tissues in the fruit fly embryo. These enhancer prediction models were used to design synthetic enhancers for the nervous system, brain, muscle, epidermis and gut.[65]
See also
References
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- ^ Bernadro P. de Almeida, Franziska Reiter, Michaela Pagani, Alexander Stark (2022). DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers. Nat Genet. 54(5):613-624
- ^ Bernardo P. de Almeida, Christoph Schaub, Michaela Pagani, Stefano Secchia, Eileen E. M. Furlong, Alexander Stark (2023): Targeted design of synthetic enhancers for selected tissues in the Drosophila embryo. Nature. DOI: 10.1038/s41586-023-06905-9
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External links
- Enhancer+Elements,Genetic at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- TFSEARCH
- JASPAR
- ReMap
- ENCODE threads explorer Enhancer discovery and characterization. Nature