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

転写阻害剤は、遺伝子の転写を抑制することができます。それらは、DNA上の調節配列に結合する明確なドメインと、転写を抑制する別のドメインを持っています。
これらのタンパク質は、さまざまなメカニズムを通じて転写を阻害することができます。最も単純なのは、アクチベーターがシス調節配列に結合するのを、いくつかの異なるメカニズムのいずれかを通じてブロックすることです。
場合によっては、阻害剤が調節配列に競合的に結合し、それによって活性化剤の結合を防ぎます。他のものでは、阻害剤は活性化因子結合部位の近くの部位に結合し、そのリプレッサードメインは活性化因子と相互作用して、活性化因子が調節配列に結合するのを防ぎます。 
阻害剤は、DNA上の一般的な転写因子の結合部位に競合的に結合し、転写機構の組み立てをブロックすることもできます。
阻害剤は、自身の抑制性シス制御配列にも結合することができ、制御領域に活性化剤が存在する場合でも転写の開始を防ぎます。
転写阻害剤が使用する最も一般的なメカニズムの一つは、そのリプレッサードメインを使用して、コリプレッサーとして知られるタンパク質をリクルートすることです。コリプレッサーは、転写を阻害する可能性のある酵素活性を持つことがよくあります。 
多くのコプレッサーは、ヒストン脱アセチル化酵素、ヒストンメチルトランスフェラーゼ、およびその他のクロマチンリモデラーとして機能します。これらの修飾により、ヌクレオソーム内のDNAが緊密に充填され、転写因子とポリメラーゼの調節部位へのアクセスが制限され、それによって転写が阻害されます。

<ol>
	<li>Lodish H、Berk A、Zipursky SL、et al. 分子細胞生物学。ニューヨーク:WHフリーマン;2000. セクション 10.7、真核生物の転写制御の分子メカニズム。から入手可能 https://www.ncbi.nlm.nih.gov/books/NBK21677/</li>
	<li>Hanna-Rose, W., & Hansen, U. (1996).真核生物転写抑制因子の能動的抑制機構。遺伝学の動向, 12(6), 229–234.土井:10.1016/0168-9525(96)10022-6</li>
	<li>レンカウィッツ、R.(1990)。真核生物における転写抑制。遺伝学の動向, 6, 192–196.土井:10.1016/0168-9525(90)90176-7</li>
</ol>

真核生物の転写阻害剤

Eukaryotic Transcription Inhibitors

胚発生や細胞成長制御などの特定の生化学プロセスは、特定の遺伝子の抑制に依存します。 真核生物の転写阻害剤として知られるDNA結合タンパク質は、真核生物の遺伝子発現の抑制を制御します。細胞内の必要な場所と時間にこれらの阻害剤が存在することは、ホルモンの存在と他の細胞からの追加シグナルによって引き起こされます。

真核生物の転写阻害剤には、通常、DNA結合ドメインとリプレッサー ドメインという2つの異なるドメインが含まれています。転写阻害剤のリプレッサードメインは、基底転写調節因子、アクチベーター、コアクチベーター、コリプレッサーなどの他のタンパク質に結合できます。 抑制ドメインは、アラニンに富むドメイン、グルタミンに富むドメイン、プロリンに富むドメインなど、構成アミノ酸に基づいて漠然と分類できます。これらは、酸性ドメインまたは塩基性ドメイン、および親水性ドメインまたは疎水性ドメインとして分類することもできます。これらのドメインは交換可能であることが多く、異なるリプレッサー ドメインが同じDNA結合ドメインと結合する可能性があります。

真核生物の転写阻害剤は、DNA結合の阻害、活性化のブロック、遺伝子サイレンシングという3つの主要なメカニズムを通じてその機能を実行できます。

DNA結合の阻害により、アクチベーターがプロモーターまたはエンハンサー部位に結合することが妨げられるか、転写開始複合体が転写開始部位またはTATAボックスに結合することが妨げられます。 これは、阻害剤の調節部位または開始部位への結合を通じて、または阻害ドメインと活性化因子、共活性化因子、または転写機構に関与するタンパク質との結合を通じて起こる可能性があります。例えばヒトでは、転写阻害剤NF-Eが胎児γ-グロビン遺伝子のCCAATボックスに結合し、活性化因子CP1の結合を阻害します。

活性化をブロックすると、プロモーターまたはエンハンサーに結合した転写活性化因子からのシグナルが転写開始部位に到達することが妨げられます。 これは、阻害剤myc-PRFがプロモーターの隣に結合するc-mycの制御のように、阻害剤がプロモーターまたはエンハンサーに隣接する部位に結合する場合に発生する可能性があります。 また、阻害剤がDNAに結合した活性化剤に結合することによっても発生する可能性があります。 このタイプの抑制は、酵母の阻害剤GAL80がプロモーターに結合しているときに活性化剤GAL4に結合するときに発生します。

遺伝子サイレンシングは、阻害剤が機構を構成するタンパク質の 1 つと転写開始部位近くのDNA上の部位に同時に結合することで転写開始複合体をロックまたは混乱させ、それによって転写機構を固定するときに発生します。例えば、酵母において、阻害剤α-2は、活性化剤GRMおよびGRMの結合部位に隣接するDNA配列に二量体として結合することにより、接合型a特異的遺伝子を不活性化する。

胚発生や細胞増殖調節などの特定の生化学的プロセスは、特定の遺伝子の抑制に依存しています。

Education

JoVE Core

Molecular Biology

分子生物学

Unit 1

ユニット1

Gene Expression

遺伝子発現

KEY TERMS AND CONCEPTS

主要用語と概念

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

How Transcription Factors Bind DNA

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...

operons

Operons in Bacterial Gene Control

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

How Transcription Activators Turn Genes On

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

Reprogramming Cells into Stem Cells

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

JoVE Core 分子生物学は、明確で簡潔なアニメーション ビデオ レッスンを通じて細胞の分子プロセスを紹介します。さらに、科学者の実際のビデオでは、これらの概念の応用が現代の研究室での実際の実験を通じて実証されています。

How Eukaryotic Gene Repressors Work

Description

Transcript

Tags