Silencer (genetics)
In genetics, a silencer is a DNA sequence capable of binding transcription regulation factors, called repressors.
[5] 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.
Though these two regulatory elements work against each other, both sequence types affect the promoter region in very similar ways.
[6] 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.
The lac operon in the prokaryote E. coli consists of genes that produce enzymes to break down lactose.
All cells in a eukaryotic organism have the same DNA but are specified through differential gene expression, a phenomenon known as genetic totipotency.
[9] Looping brings silencers in close proximity to the promoters to ensure that groups of proteins needed for optimal gene expression will work together.
[10] Silencers, being encoded in the genome, are susceptible to such alterations which, in many cases, can lead to severe phenotypical and functional abnormalities.
[12] In humans, a deficiency in the REST/NSRF silencer element has been correlated to Huntington's disease due to the decrease in the transcription of BDNF.
Furthermore, ongoing studies indicate that NRSE is involved in the regulation of the ANP gene, which when over expressed, can lead to ventricular hypertrophy.
These silencer elements also regulate the expression of genes that do not induce neuron-specific proteins and studies have shown the extensive impact these factors have in cellular processes.
In Xenopus laevis, RE1/NRSE and REST/NRSF dysfunction or mutation demonstrated significant impact on neural tube, cranial ganglia, and eye development.
[12] The lack of these factors result in a decreased production of bone morphogenetic protein (BMP), which translates into a deficient development of the neural crest.
[12] Hence, the effects of NRSE and NRSF are of fundamental importance for neurogenesis of the developing embryo, and also in the early stages of ectodermal patterning.
Ultimately, inadequate functioning of these factors can result in aberrant neural tube, cranial ganglia, and eye development in Xenopus.
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.
REST/NRSF is an important silencer element that binds to regulatory regions to control the expression of certain proteins involved in neural functions.
The mechanistic actions of huntingtin are still not fully understood, but a correlation between Htt and REST/NRSF exists in HD development.
In addition to the lack of repression due to the inactive REST/NRSF, mutated huntingtin protein can also decrease the transcription of the brain-derived neurotropic factor (BDNF) gene.
Current research has linked RE1/NRSE activity with the regulation of the expression of the atrial natriuretic peptide (ANP) gene.
[13] Hence, the regulatory activity of both NRSE and NRSF in mammals prevents not only neural dysfunctions but also physiological and phenotypical abnormalities in other non-neuronal regions of the body.
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.
