Silencer (genetics)

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.

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.

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.

There are several differences in the regulation of metabolic control in eukaryotes and in prokaryotes. Prokaryotes vary the numbers of specific enzymes made in their cells in order to regulate gene expression, which is slow metabolic control, and also regulate enzymatic pathways through mechanisms such as feedback inhibition and allosteric regulation, which is rapid metabolic control. The genes of prokaryotes are grouped together based on similar functions into units called operons which consist of a promoter and an operator. The operator is the binding site for the repressor and thus has a function equivalent to the silencer region in Eukaryotic DNA. When a repressor protein is bound to the operator, RNA polymerase cannot bind to the promoter to initiate the transcription of the operon.

Eukaryotes have a much larger genome and thus have different methods of gene regulation than in prokaryotes. All cells in a eukaryotic organism have the same DNA but are specified through differential gene expression, a phenomenon known as genetic totipotency. However, in order for a cell to express the genes for proper functioning, the genes must be closely regulated to express the correct properties. Genes in eukaryotes are controlled on the transcriptional, post-transcriptional, translational, and post-translational levels. On the transcriptional level, gene expression is regulated by altering transcription rates. Genes that encode proteins include exons which will encode the polypeptides, introns that are removed from mRNA before the translation of proteins, a transcriptional start site in which RNA polymerase binds, and a promoter.

Silencers in eukaryotes control gene expression on a transcriptional level in which the mRNA is not transcribed. These DNA sequences may act as either silencers or enhancers based on the transcription factor that binds to the sequence and binding of this sequence will prevent promoters such as the TATA box from binding to RNA polymerase. A repressor protein may have regions that bind to the DNA sequence as well as regions that bind to the transcription factors assembled at the promoter of the gene which would create a chromosome looping mechanism. Looping brings silencers in close proximity to the promoters to ensure that groups of proteins needed for optimal gene expression will work together.

Furthermore, ongoing studies indicate that NRSE is involved in the regulation of the ANP gene, which when over expressed, can lead to ventricular hypertrophy. Mutations in the Polycomb-group (PcG) complexes also presented significant modifications in physiological systems of organisms. Hence, modification in silencer elements and sequences can result in either devastating or unnoticeable changes.

Huntington's disease (HD) is an inherited neurodegenerative disorder, with symptoms emerging during an individual“s mid-adulthood. The most noticeable symptoms of this progressive disease are cognitive and motor impairments, as well as behavioral alterations. These impairments can develop into dementia, chorea, and eventually death. At the molecular level, HD results from a mutation in the huntingtin protein (Htt). More specifically, there is an abnormal repetition of a CAG sequence towards the 5“-end of the gene, which then leads to the development of a toxic polyglutamine (polyQ) stretch in the protein. The mutated Htt protein affects an individual“s proper neural functions by inhibiting the action of REST/NRSF.

The Polycomb-group (PcG) regulatory complexes are known for their influence in the epigenetic regulation of stem cells, especifically in hematopoietic stem cells. The Polycomb Repressive Complex 1 (PRC 1) is directly involved in the process of hematopoiesis, and functions together with, for example, the PcG gene ”Bmi1‘. Studies in mice indicate that organisms with mutated ”Bmi1‘ demonstrate deficient mitochondrial functioning, and also hindered the ability of hematopoietic cells to self-renew. Likewise, mutations in PRC2 genes were related to hematological conditions such as acute lymphoblastic leukemia (ALL), which is a form of leukemia. Hence, Polycomb-group genes and proteins are involved in the proper maintenance of hematopoiesis in the body.

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