Tv Enhancer

[Autumn Pitz]

TheDepartment of Anatomy and Cell Biology of the GW School of Medicine and Health Sciences offers two pre-medicine academic enhancer programs for candidates interested in applying to medical schools or biomedical sciences Ph.D. programs. Both programs are designed to enhance competitiveness of applications to medical school or to transition to an advanced graduate degree in the biomedical sciences.

Both academic enhancer programs have a clinically oriented curriculum with a problem-based learning approach that focuses on basic medical sciences taught to first-year medical students. Since the GCATS program constitutes the first year of the M-ATS curriculum, GCATS students with a minimum GPA of 3.0 can submit an application to transfer their 19 credits from GCATS to the M-ATS program.

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Distant-acting tissue-specific enhancers, which regulate gene expression, vastly outnumber protein-coding genes in mammalian genomes, but the functional importance of this regulatory complexity remains unclear1,2. Here we show that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. We used genome editing to create 23 mouse deletion lines and inter-crosses, including both single and combinatorial enhancer deletions at seven distinct loci required for limb development. Unexpectedly, none of the ten deletions of individual enhancers caused noticeable changes in limb morphology. By contrast, the removal of pairs of limb enhancers near the same gene resulted in discernible phenotypes, indicating that enhancers function redundantly in establishing normal morphology. In a genetic background sensitized by reduced baseline expression of the target gene, even single enhancer deletions caused limb abnormalities, suggesting that functional redundancy is conferred by additive effects of enhancers on gene expression levels. A genome-wide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse tissues revealed that mammalian genes are very commonly associated with multiple enhancers that have similar spatiotemporal activity. Systematic exploration of three representative developmental structures (limb, brain and heart) uncovered more than one thousand cases in which five or more enhancers with redundant activity patterns were found near the same gene. Together, our data indicate that enhancer redundancy is a remarkably widespread feature of mammalian genomes that provides an effective regulatory buffer to prevent deleterious phenotypic consequences upon the loss of individual enhancers.

Enhancers are short sections of DNA that, when bound by specific proteins, regulate the level of transcription of a target gene. Len Pennacchio and colleagues examine the impact of enhancer redundancy on gene regulation in mouse limb development by deleting one or a combination of ten highly conserved enhancers located near seven genes that are required for limb development. While none of the ten individual enhancer deletions resulted in noticeable changes in limb morphology, the deletion of pairs of enhancers near the same genes resulted in altered limb development phenotypes. Analysing mouse ENCODE data, the authors find that enhancers near the same developmentally expressed gene commonly show similar activity patterns in the same tissue. They provide a statistical framework for estimating the number of enhancers that regulate each gene during development.

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]

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.[13] The same mechanism holds true for silencers in the eukaryotic genome. Silencers are antagonists of enhancers that, when bound to its proper transcription factors called repressors, repress the transcription of the gene. Silencers and enhancers may be in close proximity to each other or may even be in the same region only differentiated by the transcription factor the region binds to.

An enhancer may be located upstream or downstream of the gene it regulates. Furthermore, an enhancer does not need to be located near the transcription initiation site to affect transcription, as some have been found located several hundred thousand base pairs upstream or downstream of the start site.[14] Enhancers do not act on the promoter region itself, but are bound by activator proteins as first shown by in vivo competition experiments.[15][16] Subsequently, molecular studies showed direct interactions with transcription factors and cofactors, including the mediator complex, which recruits polymerase II and the general transcription factors which then begin transcribing the genes.[17][18] Enhancers can also be found within introns. An enhancer's orientation may even be reversed without affecting its function; additionally, an enhancer may be excised and inserted elsewhere in the chromosome, and still affect gene transcription.[7] That is one reason that introns polymorphisms may have effects although they are not translated.[citation needed] Enhancers can also be found at the exonic region of an unrelated gene[19][20][21] and they may act on genes on another chromosome.[22]

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 transcriptioninitiation, but generally have low basal activity.[27] Other important cis-regulatory modules are localized in DNA regions that are distant from the transcription start sites. These include enhancers, silencers, insulators and tethering elements.[28] Among this constellation of elements, enhancers and their associated transcription factors have a leading role in the regulation of gene expression.[29] 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.[30]

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.[31] 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.[30] 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.[31]

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).[32] Several cell function specific transcription factors (there are about 1,600 transcription factors in a human cell[33]) generally bind to specific motifs on an enhancer[34] 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.[35]

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 the ancestors of chimpanzees.[citation needed]

An enhancer near the gene GADD45g has been described that may regulate brain growth in chimpanzees and other mammals, but not in humans.[41] 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]

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