In genetics, a silencer is a DNA sequence capable of binding transcription regulation factors, called repressors. DNA contains genes and provides the template to produce messenger RNA (mRNA). That mRNA is then translated into proteins. When a repressor protein binds to the silencer region of DNA, RNA polymerase is prevented from transcribing the DNA sequence into RNA. With transcription blocked, the translation of RNA into proteins is impossible. Thus, silencers prevent genes from being expressed as proteins. RNA polymerase, a DNA-dependent enzyme, transcribes the DNA sequences, called nucleotides, in the 3' to 5' direction while the complementary RNA is synthesized in the 5' to 3' direction. RNA is similar to DNA, except that RNA contains uracil, instead of thymine, which forms a base pair with adenine. An important region for the activity of gene repression and expression found in RNA is the 3' untranslated region. This is a region on the 3' terminus of RNA that will not be translated to protein but includes many regulatory regions. Not much is yet known about silencers but scientists continue to study in hopes to classify more types, locations in the genome, and diseases associated with silencers.
Functionality
Locations within the genome
A silencer is a sequence-specific element that induces a negative effect on the transcription of its particular gene. There are many positions in which a silencer element can be located in DNA. The most common position is found upstream of the target gene where it can help repress the transcription of the gene. This distance can vary greatly between approximately -20 bp to -2000 bp upstream of a gene. Certain silencers can be found downstream of a promoter located within the intron or exon of the gene itself. Silencers have also been found within the 3 prime untranslated region (3' UTR) of mRNA.
Types
Currently, there are two main types of silencers in DNA, which are the classical silencer element and the non-classical negative regulatory element (NRE). In classical silencers, the gene is actively repressed by the silencer element, mostly by interfering with general transcription factor (GTF) assembly. NREs passively repress the gene, usually by inhibiting other elements that are upstream of the gene. Of the NREs, there are certain silencers that are orientation-dependent meaning that the binding factor binds in a particular direction relative to other sequences. Promoter-dependent silencers are understood to be silencer elements because they are position and orientation-dependent but must also use a promoter-specific factor. There has been a recent discovery of Polycomb-group Response Elements (PREs), which can allow and inhibit repression depending on the protein bound to it, and the presence of non-coding transcription.
Mechanisms
For classical silencers, the signaling pathway is relatively simple. Since repression is active, silencer elements target the assembly of GTFs, necessary for transcription of the gene. These silencer elements are mostly located upstream of the gene and can vary between short and long distances. For long-range silencers, it has been observed that the DNA will form a loop in order to bring the silencer closer to the promoter and loop out the interfering DNA. Silencers also target helicase sites in the DNA that are rich in adenine and thymine (AT) and prone to unwinding the DNA, allowing room to initiate transcription. The inhibited helicase activity leads to the inhibition of transcription. This is commonly seen in the human thyrotropin-β gene promoter. NREs can induce a bend in the promoter region to block interactions, as seen when an NRE binds to Yin-Yang 1 (YY1), and flank regulatory signals or promoter regions as well. When the silencer region is located within an intron, there can be two types of repressions. First, there can be a physical blockage of a splice site. Second, there can be a bend in the DNA that will inhibit RNA processing. When located in the exon or the untranslated region, the silencer will mainly be classical or position-dependent. However, these silencers can carry out their activity prior to transcription. Most silencers are constitutively expressed in organisms, only allowing activation of a gene by either inhibiting the silencer or by activating an enhancer region. The best example of this is the Neuronal-Restrictive Silencer Factor (NRSF) that is produced by the REST gene. The REST gene produces NRSF in order to repress the transcription of neuronal genes that are essential for localization of neuronal tissue. When a silencer represses REST, NRSF is also inhibited, allowing for the transcription of neuronal genes.
Similarities with enhancers
Another regulatory element located upstream of the gene is an enhancer. Enhancers function as a "turn on" switch in gene expression and will activate the promoter region of a particular gene while silencers act as the "turn off" switch. Though these two regulatory elements work against each other, both sequence types affect the promoter region in very similar ways. Because silencers have not been thoroughly identified and analyzed, the extensive research on enhancers has aided biologists in understanding the mechanics of the silencer. Enhancers can be found in many of the same areas that silencers are found, such as upstream of the promoter by many kilobase pairs, or even downstream within the intron of the gene. DNA looping is also a model function used by enhancers in order to shorten the proximity of the promoter to the enhancer. Enhancers also function with transcription factors in order to initiate expression, much like silencers can with repressors.
In prokaryotes and eukaryotes
Prokaryotes
… excerpt ends here. Continue reading the full article.
