Regulation of gene expression

Gene Regulation designated in biology, the control of the activity of genes, or more precisely, the control of gene expression. It determines the concentration in which the encoded by the gene protein in the cell is to be present. There are several levels at which the regulation can take place: As the " gene expression ", the entire process of converting the information contained in the gene is referred to in the corresponding gene product. This process involves several steps. At each of these steps regulatory factors can influence and control the process.

In prokaryotes gene regulation in large part an adaptation to a changing environment, for example to a decreased oxygen or nutrient supply is changing. Eukaryotic cells are up to the protists less reliant to respond to fluctuating environmental conditions, but have for the difficult task of controlling the development of multicellular organisms. For this purpose it must be ensured that at the right time in the right in the right tissue cells the necessary genes to be activated. In differentiated cells, the fixed design expression program then has significantly less regulatory requirements.

The basic principles of gene regulation are the same in all cells, it is, however, in both prokaryotes and eukaryotes, respectively characteristics. For example, genes are organized in operons in bacteria, which do not occur in eukaryotes. Contrast, eukaryotes have mechanisms for processing of transcripts that provide additional starting points of regulatory factors.

In operon is divided into positive and negative regulation of regulation. In the positive regulation of the RNA polymerase requires an activator that binds to the DNA, so that the transcription can be performed. In the negative regulation of a repressor binds to the DNA and the RNA polymerase can not transcribe the gene. In addition, certain substrates, the activators and repressors activate (activator / repressor can bind to the DNA) or inactivate (activator / repressor dissociates from DNA). Induction occurs when the substrate causes a translation (and hence gene expression ) can be carried out ( inactivate the repressor and the activation of the activator ). Repression means the substrate prevents gene expression (activator or repressor is inactivated enabled).

Steps of gene expression

In the following steps of gene expression, the regulation will be implemented:

• Chromatin
• Initiation of transcription
• Termination of transcription
• Capping ( in eukaryotes )
• Polyadenylation ( in eukaryotes )
• Splicing ( in eukaryotes )
• Transport into the cytoplasm ( in eukaryotes )
• Stability of the mRNA in the cytoplasm of
• Initiation of translation
• Post-translational modifications of the synthesized proteins

Chromatin

In eukaryotes, the genomic DNA is partially wrapped around the histones. The modification of histones causing a change in the deployed and available for transcription regions of the DNA. The DNA methylation inactivates genes in eukaryotes.

Initiation of transcription

By controlling the transcription restart sequence the general decision is made whether the gene is expressed ( read ) is or not, and to some extent already, how many mRNA molecules are produced. This decision is made at the regulatory sequences. There are areas of DNA. Near the gene, or even further away can be ( the promoter ), but which are themselves not transcribed At these regulatory sequences may bind proteins that activate or inhibit transcription ( repress ). These key proteins called transcription factors, and they allow the cell genes by a fundamental mechanism on or off. A transcription factor that promotes the binding of RNA polymerase is referred to as an activator. A transcription factor that inhibits its binding, is called repressor. The corresponding repressive DNA sequences are referred to as silencers.

Upon binding of specific transcription factors to the promoter or enhancers, there is a change in the conformation of chromatin. This allows other proteins, the so-called basal transcription factors, as well as to bind to the DNA. The basal transcription factors then recruit the RNA polymerase and transcription of the gene is started. The specificity factors are proteins that modulate the binding specificity of the RNA polymerase. A repressor binds to the regulatory regions of DNA, preventing that attach other transcription factors and thus hinders the activation of the gene. Another form of repression is the so-called transcriptional interference. This is located in front of the promoter of the gene, a second promoter. If this is active, attaches itself to these, the RNA polymerase to synthesize and non-coding RNA. By this transcription, the transcription of the gene itself is prevented. A special case of transcriptional regulation is the catabolite repression.

Termination of transcription

For the termination of transcription different regulatory mechanisms have in pro-and eukaryotes evolved. The efficiency of termination is crucial to decide how many mRNA molecules can arise from the gene, because if the polymerase does not drop fast enough from the DNA strand, can, roughly speaking, do not move up the next polymerase molecule and the production of mRNA molecules is slower.

Termination in prokaryotes

In prokaryotes, a distinction the Rho- independent and Rho -dependent termination. In addition there is a mechanism in which the polymerase soon after transcription start again falls by the DNA attenuation.

• Simple Termination: Rho - independent or simple termination uses termination at the "end " of the gene or of the transcript, which consist of a GC-rich section and a series of uridine residues, which together form a hairpin structure, followed by several uridines to bind Hfq. You have to imagine this as a loop which thus comes about that interconnect nucleotides of one strand of nucleotides of the same strand as the double helix, describing a loop. When the RNA polymerase that has these nucleotide strand yes just created, interacts with the loop, it stops and falls on the DNA strand. This RNA do not have a polyA tail.
• Rho -dependent termination: Rho -dependent termination, and uses an additional protein, the Rho factor. Is a hexameric protein of 70 to 80 nucleotides embrace the nascent ( resulting ) RNA strand and is activated by interaction with the DNA. Under consumption of ATP, the rho factor moved to the newly synthesized mRNA along in the direction of the DNA until it encounters the RNA polymerase. He separates the DNA -RNA hybrid in which establishes the RNA polymerase and the RNA hydrolyzed ( helicase function). Thus, the RNA polymerase and initiating transcription of drops is completed. The Rho factor must therefore theoretically faster at the RNA move along as the polymerase. However, the polymerase does not move continuously fast to the DNA (equivalent to the rate of RNA synthesis ) along, but slows down again and again in between what the rho factor allows to catch up.
• Attenuation: by forming a secondary structure is interrupted in the case of RNA synthesis Tryptohanmangels. When a tryptophan - containing peptide ( at the simultaneous transcription and translation ) can not be established due to lack of tryptophan, an RNA secondary structure that interrupts the transcription forms.

Termination in eukaryotes

The three different eukaryotic RNA polymerase (I, II and III) use different Terminationsmechanismen that are not particularly well studied. However, there are some similarities and differences for the termination in bacteria known:

• RNA polymerase I transcribes rRNA genes, requires a termination factor Rho-like, which, however, does not bind to the RNA, but downstream to the DNA.
• The RNA polymerase II which transcribes the mRNA transcription will probably end until the polyadenylation occurs (see next section).
• RNA polymerase III that transcribes tRNA genes terminates transcription by the incorporation of a number of uracil nucleotides.

RNA processing

Capping

Capping the 7-methyl guanosine is synthesized on the 5'- end of the pre-mRNA, which affects the stability and the subsequent translation of the RNA. The 5 'cap structure facilitates the attachment of the final mRNA to the ribosome in translation ( initiation).

Polyadenylation

Almost all mRNAs of animal cells carry a poly (A ) tail. The process of attachment of this tail is referred to as polyadenylation. Similarly to the termination of transcription, the strength of the transcription of the efficiency of the Polyadenylierungsmechanismus depends '. When the attachment of the poly ( A) tail is not functioning properly, the mRNA is not as accumulated in the nucleus, but quickly degraded. Here, then, can fix regulatory factors.

Splice

In splicing introns are removed from the pre-mRNA, and the remaining exons together. For this operation, which is performed by the spliceosome, there are many alternatives genes, also called alternative splicing. Regulatory factors determine which introns are spliced ​​and thus determine how the finished mRNA will look like.

Transport into the cytoplasm

The transport of the mRNA to the cytoplasm occurs through pores in the nuclear envelope. Only fully processed mRNAs are funneled to the 5'- end first through the nuclear pore and immediately occupied with ribosomes in the cytoplasm. For this purpose, mRNA is assembled with various proteins to a hnRNP - complex which can migrate as a finished mRNP through the nuclear pore. The efficiency of this operation determines the speed and the quantity of finished mRNAs enter the cytoplasm, and can be regulated by factors.

Initiation of translation

The start of translation is in some genes of the most important regulatory step, with others he hardly plays a role. In eukaryotes as well as in prokaryotes, first, an existing pre-initiation complex of different proteins is formed, which interacts with the small subunit of a ribosome. This complex then identifies the translation start site. The possibilities of regulation are here again very diverse. These range from the use of specific initiation factors to an overall deactivation of the initiation, which can be achieved by using a serine residue of a protein of the preinitiation complex ( eIF2 ) is phosphorylated.

The translation of certain mRNAs may also be blocked by anti-sense RNA complementary anneal to the 5 'region of the RNA and thereby preventing the binding of the small ribosomal subunit. Also microRNAs play an important role in translational regulation. During the translation, there is, for example, in prokaryotes, the trp operon, the attenuation as a regulatory mechanism.

Stability of the mRNA

After the initiation of the transcription, and ( in some genes ) of the initiation of translation regulating the half-life of an mRNA is a further regulation process. The concentration of an mRNA depends on how fast it is produced and how quickly they will be dismantled. If an mRNA is very stable, the protein production can take place even long after the inactivation of the gene. For proteins that need to be "turned off" quickly in case of need, so may no longer be present, therefore, a short-lived mRNA beneficial, eg with AUUUA sequences that accelerate through binding of RNase degradation. The stability of an mRNA is determined inter alia by the fact that the 3 'untranslated region of the transcript occur several AUUUA sequences. The more of them there are, the faster the RNA is degraded. Another important factor for the stability of the mRNA is the length of the poly ( A) tail. The shorter of these, the lower the half-life.

Most bacterial mRNAs have only a half-life of a few minutes. Eukaryotic cells have differentiated to a large extent less Genregulationsbedarf (see above), the mRNA molecules of many genes to achieve half-lives of several hours. Other eukaryotic genes that are only needed in the short term (eg, hormones or cytokines ) are expressed impulsively.

For short-acting genes, proteins contain amino acids or amino acid sequences that accelerate the degradation of a protein, such as certain amino acids after the N- End Rule, PEST sequences or protease cleavage sites.

Epigenetic Regulation

There are genes in which the information as to whether the gene is to be activated or repressed in the daughter cells, is not present in the gene directly, or is mediated by the gene, but by the transcription factors that regulate it. The transcription factors are, so to speak " mitvererbt ". These mechanisms deal epigenetics and imprinting.

Specific regulatory mechanisms

• Autoregulation
• Gene regulation in developmental processes

Certain genes are always expressed and thus have no need for regulation, these are referred to as housekeeping genes.

Gene regulatory regions

In gene or gene belonging there are certain areas that are responsible for regulation. These are

• Promoter
• Operator
• Cis- elements such as, silencers or enhancers