Name: how eukaryotic gene repressors work
Uploaded: 2020-11-23T11:47:37.000Z
Duration: 1 min 52 s
Channel: JoVE

Transkriptionsinhibitoren sind in der Lage, die Transkription eines Gens zu unterdrücken. Sie haben eine ausgeprägte Domäne, die an regulatorische Sequenzen auf der DNA bindet, und eine weitere Domäne, die die Transkription unterdrückt.
Diese Proteine können die Transkription durch verschiedene Mechanismen hemmen. Die einfachste besteht darin, einen Aktivator durch einen von mehreren verschiedenen Mechanismen daran zu hindern, an seine cis-regulatorische Sequenz zu binden.
In einigen Fällen bindet der Inhibitor kompetitiv an die regulatorische Sequenz und verhindert dadurch die Bindung des Aktivators. In anderen Fällen bindet der Inhibitor an eine Stelle in der Nähe der Aktivator-Bindungsstelle, und seine Repressordomäne interagiert mit dem Aktivator, um zu verhindern, dass er an die regulatorische Sequenz bindet. 
Ein Inhibitor kann auch kompetitiv an die Bindungsstellen allgemeiner Transkriptionsfaktoren auf der DNA binden und den Zusammenbau der Transkriptionsmaschinerie blockieren.
Inhibitoren können auch an ihre eigenen inhibitorischen cis-regulatorischen Sequenzen binden und so die Initiierung der Transkription verhindern, selbst wenn ein Aktivator auf der regulatorischen Region vorhanden ist.
Einer der häufigsten Mechanismen, die von Transkriptionsinhibitoren verwendet werden, besteht darin, seine Repressordomäne zur Rekrutierung von Proteinen zu verwenden, die als Co-Repressoren bekannt sind. Co-Repressoren haben oft enzymatische Aktivitäten, die die Transkription hemmen können. 
Viele Co-Repressoren fungieren als Histon-Deacetylasen, Histon-Methyltransferasen und andere Chromatin-Remodeler. Diese Modifikationen führen zu einer engen Packung der DNA im Nukleosom und schränken den Zugang von Transkriptionsfaktoren und Polymerase zu ihren regulatorischen Stellen ein, wodurch die Transkription gehemmt wird.

<ol>
	<li>Lodish H, Berk A, Zipursky SL, et al. Molekulare Zellbiologie. 4. Auflage. New York: W. H. Freeman; 2000. Abschnitt 10.7, Molekulare Mechanismen der eukaryotischen Transkriptionskontrolle. Verfügbar ab: https://www.ncbi.nlm.nih.gov/books/NBK21677/</li>
	<li>Hanna-Rose, W., & Hansen, U. (1996). Aktive Repressionsmechanismen von eukaryotischen Transkriptionsrepressoren. Trends in der Genetik, 12(6), 229–234. doi:10.1016/0168-9525(96)10022-6</li>
	<li>Renkawitz, R. (1990). Transkriptionelle Repression in Eukaryoten. Trends in der Genetik, 6, 192–196. doi:10.1016/0168-9525(90)90176-7</li>
</ol>

inhibitoren der eukaryotischen transkription

Eukaryotic Transcription Inhibitors

Bestimmte biochemische Prozesse, wie die embryonale Entwicklung und die Regulation des Zellwachstums, hängen von der Unterdrückung spezifischer Gene ab. DNA-bindende Proteine, bekannt als Inhibitoren der eukaryotischen Transkription, regulieren die Repression der Genexpression bei Eukaryoten. Das Vorhandensein dieser Inhibitoren an der erforderlichen Stelle und Zeit in der Zelle wird durch das Vorhandensein von Hormonen und zusätzlichen Signalen aus anderen Zellen ausgelöst.

Eukaryotische Transkriptionsinhibitoren enthalten in der Regel zwei unterschiedliche Domänen, eine DNA-Bindungsdomäne und eine Repressordomäne. Repressordomänen von Transkriptionsinhibitoren können an andere Proteine binden, wie zum Beispiel an basale Transkriptionsregulatoren, Aktivatoren, Co-Aktivatoren und Co-Repressoren. Repressordomänen können grob auf der Basis ihrer Aminosäurenzusammensetzung kategorisiert werden, wie alaninreiche Domänen, glutaminreiche Domänen und prolinreiche Domänen. Sie können auch als saure oder basische Domänen sowie als hydrophile oder hydrophobe Domänen eingeteilt werden. Diese Domänen sind oft austauschbar, und verschiedene Repressordomänen können sich mit derselben DNA-Bindungsdomäne verbinden.

Eukaryotische Transkriptionsinhibitoren können ihre Funktion durch drei Hauptmechanismen ausüben – Hemmung der DNA-Bindung, Blockierung der Aktivierung und Gen-Stillegung.

Die Hemmung der DNA-Bindung verhindert entweder, dass der Aktivator an die Promotor- oder Enhancer-Stelle bindet, oder sie kann verhindern, dass der Transkriptionsinitiationskomplex an die Transkriptionsstartstelle oder die TATA-Box bindet. Dies kann entweder durch die Bindung des Inhibitors an die regulatorische oder Startstelle oder durch die Assoziation der Inhibitordomäne mit Aktivatoren, Co-Aktivatoren oder an der Transkription beteiligten Proteinen erfolgen. Zum Beispiel bindet bei Menschen der Transkriptionsinhibitor NF-E an die CCAAT-Box des fetalen γ-Globin-Gens und verhindert die Bindung des Aktivators CP1.

Die Blockierung der Aktivierung verhindert, dass das Signal eines an einen Promotor oder Enhancer gebundenen Transkriptionsaktivators die Transkriptionsstartstelle erreicht. Dies kann vorkommen, wenn ein Inhibitor an eine Stelle neben dem Promotor oder Enhancer bindet, wie bei der Regulation von c-myc, wo der Inhibitor myc-PRF neben dem Promotor bindet. Es kann auch vorkommen, dass der Inhibitor an einen DNA-gebundenen Aktivator bindet. Diese Art der Repression tritt auf, wenn der Inhibitor GAL80 in Hefen an den Aktivator GAL4 bindet, wenn dieser an den Promotor gebunden ist.

Gen-Stillegung tritt auf, wenn der Inhibitor entweder das Transkriptionsinitiationskomplex verriegelt oder desorganisiert, indem er gleichzeitig an eines der Proteine, die das Maschinenwerk bilden, und an eine Stelle auf der DNA nahe der Transkriptionsstartstelle bindet und dadurch die Transkriptionsmaschinerie verankert. Zum Beispiel inaktiviert in Hefen der Inhibitor α-2 die spezifischen Gene des Paarungstyps a, indem er als Dimer an den Aktivator GRM und an DNA-Sequenzen bindet, die die Bindungsstelle von GRM umgeben.

Inhibitoren der eukaryotischen Transkription

Bestimmte biochemische Prozesse, wie die Embryonalentwicklung und die Regulation des Zellwachstums, hängen von der Unterdrückung bestimmter Gene ab. Die DNA-Bindung ...

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how eukaryotic gene repressors work

Eukaryotic gene repressors help turn specific genes off when the cell needs to control growth, development, or other biochemical processes. These DNA-binding proteins regulate gene expression in eukaryotes. Their presence at the right time and place can be triggered by hormones and signals from other cells.

Most transcription inhibitors have two main parts. One part binds DNA, and the other is a repressor domain, which helps shut down transcription. Repressor domains can connect with basal transcription regulators, activators, co-activators, and co-repressors.

These repression domains are often grouped by their amino acids, such as alanine-rich, glutamine-rich, and proline-rich domains. They can also be described as acidic or basic, and as hydrophilic or hydrophobic. Different repressor domains can often be swapped onto the same DNA-binding domain.

Eukaryotic transcription inhibitors act through three main mechanisms: inhibiting DNA binding, blocking activation, and gene silencing. Inhibiting DNA binding stops an activator from attaching to a promoter or enhancer, or it prevents the transcription initiation complex from binding the transcription start site or the TATA box. This can happen when the inhibitor binds the regulatory site or start site, or when its inhibitory domain interacts with activators, co-activators, or other transcription machinery proteins.

One example is NF-E in humans. It binds the CCAAT box of the fetal gamma-globin gene and blocks the activator CP1 from binding. Blocking activation works differently. The inhibitor can bind next to a promoter or enhancer, as in c-myc regulation, where myc-PRF binds beside the promoter. It can also bind to an activator already attached to DNA. In yeast, GAL80 binds GAL4 when GAL4 is bound to the promoter.

Gene silencing happens when the inhibitor locks or disrupts the transcription initiation complex. It does this by binding both a protein in the machinery and a DNA site near the transcription start site, which anchors the complex. In yeast, the alpha-2 inhibitor works this way to turn off mating type a-specific genes. It binds as a dimer to the activator GRM and to DNA sequences beside the GRM binding site.

How Eukaryotic Gene Repressors Work

cell specific gene expression

How Cells Switch Genes On and Off

Cells switch genes on and off to make different proteins for different jobs. In multicellular organisms, many cell types are built from the same DNA, but they do not use the same genes in the same way. This difference in gene expression helps explain why cells can look and act so differently. Liver cells are a clear example. They help detoxify blood, make bile to help digest fats, and produce proteins needed for metabolism. To do these jobs, liver cells must express a specific set of genes.

regulation of expression occurs at multiple steps

regulation-of-expression-occurs-at-multiple-steps

How Cells Control Gene Expression

Cells control gene expression at several points between DNA and protein. The most common control point is transcription. At this stage, proteins bind to short regulatory DNA sequences and can either increase or reduce transcription of the linked gene. After transcription, a precursor mRNA is made. This pre-mRNA contains exons, which code for protein, and introns, which do not. It must be processed before translation, and splicing removes the introns and joins the exons. Cells can also regulate...

cis-regulatory sequences

How Cis-Regulatory DNA Controls Transcription

Cis-regulatory sequences are short, non-coding DNA segments that control gene transcription. They sit on the same chromosome as the genes they regulate and act as binding sites for transcriptional regulators. In eukaryotes, these proteins help control gene expression patterns in different cell types. These DNA sequences can be close to a gene or thousands of bases away. When they are far from the gene in the DNA sequence, they are often brought close together in space because chromosomes are...

cooperative binding of transcription regulators

cooperative-binding-of-transcription-regulators

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Transcriptional regulators bind to cis-regulatory DNA sequences to control gene transcription. These DNA sequences are very short, usually fewer than ten nucleotide pairs long. Because they are so short, the same sequence can appear by chance in many places across the genome. Some regulators can also bind to groups of similar sequences. That raises the chance of random binding even more. To lower this risk, transcription regulators often form dimers, which are pairs of proteins that bind a DNA...

prokaryotic transcriptional activators and repressors

prokaryotic-transcriptional-activators-and-repressors

Operon Control by Activators and Repressors

Operon control in prokaryotes depends on activators and repressors. Prokaryotic genes are often arranged in groups, not one by one like in eukaryotes. Genes that help carry out the same biochemical process are placed together with their regulatory elements. This group is called an operon, and it is transcribed into a single polycistronic mRNA strand. Activators and repressors are DNA-binding proteins that control transcription in an operon. Activators bind near the promoter, which is the site...

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Operons help bacteria control groups of genes at the same time. An operon is a set of genes that are regulated together and can be turned on or off as a unit. This shared control helps bacteria respond quickly to changes in their environment. In many operons, a promoter gives RNA polymerase a place to bind and start transcription. The operon also includes a regulatory region that helps control whether the genes are expressed. When conditions change, the cell can use this setup to manage gene...

the eukaryotic promoter region

Eukaryotic Promoter Motifs and Gene Control

The eukaryotic promoter region is a stretch of DNA located upstream of a gene. It includes an RNA polymerase binding site, a transcription start site, and several cis-regulatory sequences. These DNA signals help control when transcription begins. The promoter can be divided into proximal and distal regions. The proximal promoter lies close to the gene and includes cis-regulatory sequences and the core promoter. The core promoter is the RNA polymerase binding site, and it is usually found...

co-activators and co-repressors

Chromatin Control in Gene Transcription

Chromatin control plays a major role in gene transcription in eukaryotes. Gene expression is regulated by several proteins that work together at a gene regulatory site. Some of these proteins bind directly to specific DNA sequences, while co-regulators attach to those regulators but do not bind DNA on their own. Co-regulators can act as co-activators or co-repressors, depending on the complex they join. One co-regulator may even switch roles in different settings. For example, the...

eukaryotic transcription activators

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Transcription activators are proteins that help turn genes on by promoting transcription from DNA to RNA. They often have two parts. One part binds to DNA, and the other part activates transcription. In some proteins, such as the glucocorticoid receptor and MyoD, one domain can do both jobs. The DNA-binding part recognizes specific regulatory sequences on the DNA. These binding domains are grouped into families based on their structure. Common examples include the leucine zipper, zinc finger,...

eukaryotic transcription inhibitors

Eukaryotic gene repressors help turn specific genes off when the cell needs to control growth, development, or other biochemical processes. These DNA-binding proteins regulate gene expression in eukaryotes. Their presence at the right time and place can be triggered by hormones and signals from other cells. Most transcription inhibitors have two main parts. One part binds DNA, and the other is a repressor domain, which helps shut down transcription. Repressor domains can connect with basal...

combinatorial gene control

Gene Expression by Transcription Factor Combinations

Gene expression can depend on combinations of transcription factors working together. In combinatorial gene control, several transcription factors act in a coordinated way to regulate a single gene. If one or more of these factors are missing, the level of gene expression or repression can change a lot. This kind of control helps explain how a relatively small number of transcription factors can regulate a very large number of genes. More than 30,000 genes are controlled by about 2,000 to...

induced pluripotent stem cells

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Induced pluripotent stem cells are created by reprogramming mature cells back into a stem-cell state. This process shows that specialized cells can be changed into cells with broader developmental potential. The topic is important in biology because it links cell identity, gene control, and stem cell research. These cells begin as ordinary body cells and are pushed to de-differentiate, or lose their specialized features. After reprogramming, they behave like pluripotent stem cells, which means...

master transcription regulators

MEF2C and Gene Control Cascades

MEF2C is a master transcription regulator that controls gene expression in coordinated cascades. These regulators are proteins that manage the activity of multiple genes that often work together to produce a complex outcome. When a master transcription regulator is activated, it can start a chain of transcriptional activation that supports that outcome. Master transcription regulators can act in two main ways. They may bind directly to the regulatory sequences of several genes involved in a...

epigenetic regulation

DNA Methylation and Histone Changes

Epigenetic regulation controls gene activity without changing the DNA sequence. It helps determine when genes are turned on or off in a cell. Two major epigenetic mechanisms are DNA methylation and histone modification. DNA methylation adds chemical groups to DNA, while histone changes affect how tightly DNA is packed around histone proteins. These changes can make genes easier or harder to use. In high school biology, epigenetic regulation is important for understanding how cells with the...

genomic imprinting and inheritance

Genomic Imprinting in Human Disease

Genomic imprinting affects how some inherited genes are turned on or off in human cells. Diploid organisms inherit chromosomes from both parents, and each gene usually has two alleles. In most cases, both alleles are expressed. If one allele is missing or mutated, the other can often compensate, but some genes do not work that way. In genomic imprinting, a gene or its regulatory sequence carries chemical tags, such as methyl groups, on the copy inherited from only one parent. These tags are...

key terms and concepts

Learn how eukaryotic gene repressors control transcription through DNA binding, blocking activation, and gene silencing, with clear examples from humans and yeast.

How Eukaryotic Gene Repressors Work | JoVE K12

molecular biology

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How Eukaryotic Gene Repressors Work

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