Talk:Silencer (genetics)

Proposal

Members of the group will split the work evenly by researching respected subtopics: Tara will research the evolution and functionality of silencers, Richard will research mutations in silencers and their effects, and Chris will research the mechanism behind how silencers work in genomes.

Summary

An important DNA sequence that is found in both eukaryotes and prokaryotes are silencers. Silencers are capable of binding transcription regulation factors called repressors. When repressors are bound to the silencers, RNA polymerase is prevented from transcribing these specific DNA sequences and will decrease or fully suppress RNA synthesis. If transcription is prevented, proteins cannot be synthesized because there are no mRNA templates to translate the proteins.

DNA (deoxyribonucleic acid) contains genes which are the hereditary material located in the nuclei of eukaryotic and prokaryotic cells. DNA sequences are made up of four chemical bases: adenine, guanine, cytosine, and thymine. These bases also form base pairs held together by hydrogen bonds along the double helix structure of DNA: adenine and thymine form a base pair and ctyosine and guanine form a base pair.

These base pairs also create DNA sequences that can be transcribed to form proteins. RNA polymerase, a DNA-dependent enzyme, produces RNA (ribonucleic acid) using DNA sequences as a template. This RNA will then be used for future synthesis of proteins which activates or inactivates gene expression in cells. RNA is similar to DNA except that instead of the nucleic acid thymine, RNA contains uracil which forms a base pair with adenine. Once the RNA has been transcribed from the DNA, referred to as messenger RNA or mRNA, it will be used as a template by amino acids to translate proteins.

Sungta (talk) 23:01, 20 March 2013 (UTC)

Content of Article

1. Introduction to DNA, RNA, Silencers

2. Functionality of silencers - what they do

3. Evolution of silencers across prokaryotes and eukaryotes

4. Mechanism behind silencers - how they work

5. Mutated silencers, hereditary diseases, and their effects

6. Important Silencers that have been researched extensively. Clucaj (talk) 04:57, 21 March 2013 (UTC)

Sungta (talk) 23:09, 20 March 2013 (UTC)

First Draft of Article

Introduction

An important DNA sequence that is found in both eukaryotes and prokaryotes are silencers. Silencers are capable of binding transcription regulation factors called repressors. When repressors are bound to the silencers, RNA polymerase is prevented from transcribing these specific DNA sequences and will decrease or fully suppress RNA synthesis. If transcription is prevented, proteins cannot be synthesized because there are no mRNA templates to translate the proteins.

DNA (deoxyribonucleic acid) contains genes which are the hereditary material located in the nuclei of eukaryotic and prokaryotic cells. DNA sequences are made up of four chemical bases: adenine, guanine, cytosine, and thymine. These bases also form base pairs held together by hydrogen bonds along the double helix structure of DNA: adenine and thymine form a base pair and ctyosine and guanine form a base pair.

These base pairs also create DNA sequences that can be transcribed to form proteins. RNA polymerase, a DNA-dependent enzyme, produces RNA (ribonucleic acid) using DNA sequences as a template. This RNA will then be used for future synthesis of proteins which activates or inactivates gene expression in cells. RNA is similar to DNA except that instead of the nucleic acid thymine, RNA contains uracil which forms a base pair with adenine. Once the RNA has been transcribed from the DNA, referred to as messenger RNA or mRNA, it will be used as a template by amino acids to translate proteins. Sungta (talk) 23:39, 2 April 2013 (UTC)

Functionality and Evolution of Silencers

There are several differences in the regulation of metabolic control in eukaryotes and in prokaryotes. Prokaryotes can vary the numbers of specific enzymes made in their cells in order to regulate gene expression which is a slow metabolic control. They can also regulate enzymatic pathways through mechanisms such as feedback inhibition and allosteric control which is under a rapid metabolic control. The genes of prokaryotes are grouped together based on similar functions into units called operons. Operons consist of the promoter site which allows RNA polymerase to bind for transcription, and the operator, which is the binding site for the repressor.

For example, the lac operon in the prokaryote E. coli consists of genes that produce enzymes to break down lactose; these genes are activated by the presence of lactose in the cell. The three functional genes in this operon are lacZ which produces B-galactosidase, lacY which produces permease, and lacA which produces B-galactosidase transacetylase. The repressor gene, lacI, will produce the repressor under allosteric control. When the repressor is bound to lactose, it will not bind to the operator but will allow transcription of the operon and vice versa. (Figures to follow)

Eukaryotes, which are more complex organisms than are prokaryotes because of their larger genome and multiple metabolic controls, have different methods of gene regulation than do prokaryotes. All cells in a eukaryotic organism have the same DNA, or the same genes, and is known as genetic totipotency. A human cell is capable of having 35,000 genes. However, in order for a cell to express the correct 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.

Silencers are controlled on a transcriptional level and have been found to bind to specific transcription factors called repressors that prevent the transcription of a specific DNA sequence. These DNA sequences may act as either silencers or enhancers based on the transcription factor that binds to the sequence. These eukaryotic silencers act as control regions for a specific gene's promoter that can be located up to thousands of base pairs upstream or dowstream unlike in prokaryotic genome. This discovery led to the theory that repressors may have both a DNA-binding site, which binds to the silencer, and a site to bind to transcription facotrs that are assembled at the gene's promoter. (Figure to follow)

Mutated silencers, hereditary diseases, and their effects

Mutations lead to not only observable phenotypic influences in an individual but also alterations that are undetectable phenotypically. Silencers, being encoded in the genome, are susceptible to such alterations, which, in many cases, lead to severe phenotypical and functional abnormalities. In general terms, mutations in silencer elements or regions could lead to either the inhibition of the silencer’s action or to the persisting repression of a necessary gene. Thus, leading to the expression or suppression of an undesired phenotype, which then translates into impacts on the normal functionality of certain systems in the organism. Among the many silencer elements and proteins, REST/NSRF is an important silencer factor that has a variety of impacts not only in neural but also in other areas of development. In fact, in many cases, REST/NSRF acts in conjunction with RE-1/NRSE to repress and influence non-neuronal cells. Its effects range from humans to frogs, Xenopus laevis to be more specific, having innumerous repercussions not only in phenotype but also in development. 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 overexpressed can lead to ventricular hypertrophy. Finally, in Xenopus laevis, REST/NRSF malfunction or damage has been associated to abnormal ectodermal patterning during development and significant consequences in neural tube, cranial ganglia, and eye development. Hence, modification in silencer elements and sequences can result in either devastating changes or unnoticeable ones.

REST/NSRF and Huntington’s Disease

See also: Huntingtin

Huntington’s disease (HD) is an inherited neurodegenerative disorder, which has the emergence of its symptoms 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. In 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.

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. By attaching to the REST/NRSF, the mutated huntingtin protein inhibits the action of the silencer element, and retains it in the cytosol. Thus, REST/NRSF cannot enter the nucleus and bind to the 21 base-pair RE-1/NRSE regulatory element. An adequate repression of specific target genes are of fundamental importance, since many are involved in the proper development of neuronal receptors, neurotransmitters, synaptic vesicle proteins, and channel proteins. A deficiency in the proper development of these proteins can cause the neural dysfunctions seen in Huntington’s disease. 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. BDNF influences the survival and development of neurons in the central nervous system as well as the peripheral nervous system. This abnormal repression occurs when the RE1/NRSE region within the BDNF promoter region is activated by the binding of REST/NRSF, which leads to the lack of transcription of the BDNF gene. Hence, the anomalous repression of the BDNF protein suggests a significant impact in Huntington’s disease.

REST/NRSF and Ventricular Hypertrophy in Mammals

REST/NRSF in conjunction with RE1/NRSE also acts outside the nervous system by acting as regulators and repressors. Researches have linked RE1/NRSE activity with the regulation of expression of the atrial natriuretic peptide (ANP) gene. A NRSE regulatory region is present in the 3’untranslated region of the ANP gene, and acts as a mediator for the appropriate expression of the gene. The protein encoded by the ANP gene is important during embryonic development for the maturation and development of cardiac myocytes. However, during early childhood and throughout adulthood, ANP expression is suppressed or kept to a minimum in the ventricle. Thus, an abnormal induction of the ANP gene can lead to ventricular hypertrophy, and severe cardiac consequences. In order to maintain the gene repressed, NRSF (neuron-restrictive silencer factor) or REST binds to the NRSE region in the 3’untranslated region of the ANP gene. Furthemore, the NRSF-NRSE complex recruits a transcriptional corepressor known as mSin3. Thus, leading to the activity of histone deacetylase in region, and the repression of gene expression. Therefore, studies have revealed the correlation between REST/NRSF and RE1/NRSE in regulating the ANP gene expression in ventricular myocytes. A mutation in either the NRSF or NRSE can lead to an undesirable development of ventricular myocytes, due to lack of repression, which can then cause ventricular hypertrophy. Left ventricular hypertrophy, for example, increases an individual’s chance of sudden death due to a ventricular arrhythmia resulting from the increased ventricular mass (8). In addition to the influence on the ANP gene, the NRSE sequence regulates other cardiac embryonic genes, such as BNP, skeletal α-actin, and Na, K – ATPase α3 subunit. 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.

REST/NRSF in Xenopus laevis

[The effects and influences of RE1/NRSE and REST/NRSF are significant in non-neuronal cells that require the repression or silencing of neuronal genes. 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. All of these alterations can be traced to an improper patterning of the ectoderm during Xenopus development. Thus, a mutation or alteration in either the silencing region Re1/NRSE or silencer REST/NRSF factor can disrupt the proper differentiation and specification of the neuroepithelial domain, and also hinder the formation of skin or ectoderm. Furthermore, 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. 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. Richjoo (talk) 00:28, 3 April 2013 (UTC) Richjoo (talk) 20:05, 22 March 2013 (UTC) Clucaj (talk) 22:27, 2 April 2013 (UTC)

Sungta (talk) 20:12, 2 April 2013 (UTC)

Recent Edits

My portion of the article covered the Mechanisms of Silencers. My recent edits to this portion was the inclusion of a figure, and a section on the similarities of enhancers to Silencers. I added to the mechanisms suptopic the example of REST/NRSF. I then added wikilinks throughout my section of the article. Finally, I cleaned up the citations by adding ref names and also added more citations throughout the writing instead of at the end of each paragraphClucaj (talk) 01:46, 7 April 2013 (UTC)

1. Citations were added

2. New content added to the introduction, prokaryotes/eukaryotes sections

3. Wikilinks added

4. External links added

5. Possibly copyrighted images taken down and free-use images added

Sungta (talk) 02:14, 7 April 2013 (UTC)

My portion of the article was to research mutations in silencers. Recent edits made were the addition of an additional section talking about mutations in Polycomb-group regulatory complexes. Wikilinks were added throughout the section, and external links (ANP, African clawed frog, and REST). An image of the bone marrow of a patient with acute lymphoblastic leukemia was also added. The citations were cleaned up using ref names, and the order of the sections on REST/NRSF were rearranged. Modifications in the introduction were made according to the modifications made throughout the body of the section. Richjoo (talk) 03:06, 7 April 2013 (UTC)

Classmate Edit

Your page looks really great so far. I read through your page and added some commas and rephrased a few choppy sentences. I also added some wikilinks including links to dementia and chorea. You guys have a lot of information and provide some great detail and examples. Overall I don't think you need to add any new info, or take any out. You guys have some great pictures and diagrams, but if you can find more I would say to add them to the REST/NRSF sections. Great Job! Kmcging (talk) 19:28, 11 April 2013 (UTC)

I think the page is really well organized and has great content. I only made some very minor edits. Here are some sentences that confused me.. I didn't want to change the wording in case I messed up the meaning. “Operons consist of a promoter and an operator, which is the binding site for the repressor, which regulates gene expression.” too many whiches "The operator of the lac operon in the prokaryote E. coli, which consists of genes that produce enzymes to break down lactose, is an example of a prokaryotic silencer." I assume the "which" refers to the operator, not E. coli? Unsure. "Its effects range from frogs, Xenopus laevis to be more specific, to humans, with innumerous repercussions not only in phenotype, but also in development." confusing. Regarding content suggestions, I would more clearly relate the "Functionality and Evolution of Silencers" section to silencers. Reading it, I didn't immediately know how it all came together. Also, I don't know where the Evolution part comes in. But again, awesome job. Dehringb (talk) 20:26, 11 April 2013 (UTC)

Overall I think your page is great and really well organized. I made some minor edits adding commas and adding wiki links (accidentally did it without signing in however), but I think the overall content is pretty good. I definitely wouldn't add any more information. One thing that I did notice however is that before each section you give a great deal of background information. In the beginning sections which is essentially suppose to be an overview of silencers and the contents of the article you essentially explain all about DNA and RNA making me feel as if the article was more about these two things than the actual silencers themselves. I don't know if you need to go into that much detail describing DNA and RNA. The wonderful thing about wikipedia is that if someone doesn't understand your reference to DNA then they can simply click on the link and get more background information. I do think that a little background information is necessary but maybe not to that extent and maybe you should give a better summary of silencers themselves instead of just the small paragraph at the end of the introduction. I also think that this carries over to your paragraphs about prokaryotes and eukaryotes. In each instance there is a great deal of build up before you actually start talking about silencers. In Eukaryotes in particular the first paragraph is about the eukaryotic genome and then the second is all about promoters. It may be beneficial to cut some of the unnecessary background information or try and integrate the background information into the discussion of silencers so that the reader doesn't feel they are reading two articles at once. Overall great work though. Keep it up. Lacarubb (talk) 01:39, 14 April 2013 (UTC)

References

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281776/

http://bejerano.stanford.edu/readings/public/10_Intro_TxRegReview.pdf

http://www.uic.edu/classes/bios/bios100/lecturesf04am/lect15.htm

http://www.ncbi.nlm.nih.gov/books/NBK21572/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1219314/pdf/9512455.pdf

http://www.ncbi.nlm.nih.gov/books/NBK7588/

http://www.ncbi.nlm.nih.gov/books/NBK10023/

http://www.news-medical.net/health/What-is-DNA.aspx

http://www.ncbi.nlm.nih.gov/pubmed/11238943?dopt=Abstract&holding=npg

http://www.ncbi.nlm.nih.gov/pubmed/7871435 Richjoo (talk) 20:06, 22 March 2013 (UTC) http://www.ncbi.nlm.nih.gov/pubmed/23198762 — Preceding unsigned comment added by Richjoo (talk • contribs) 16:26, 19 March 2013 (UTC)

Our group has continued to work on the Silencer (DNA) article by adding information on the structure, mechanisms, evolution, and mutations of silencers. We continue to research for more information we can add to this article. Sungta (talk) 16:11, 4 April 2013 (UTC)

Things we are continuing to do: Expand/generalize/cover all points of the article in the introduction How silencers arise (external factors, inherited factors, internal factors)

Bibliography

Brown, Terry. Genomes 3 . New York: Garland Science Pub., 2007. Print.

"Control of Genetic Systems in Prokaryotes and Eukaryotes." University of Illinois at Chicago. N.p., n.d. Web. 27 Apr 2013. <http://www.uic.edu/classes/bios/bios100/lecturesf04am/lect15.htm>.

"Eukaryotic Gene Control." Kenyon College. N.p.. Web. 27 Apr 2013. <http://biology.kenyon.edu/courses/biol114/Chap10/Chap10.html>.

"Gene Regulation in Eukaryotes "Web. 4/26/2013 <http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Promoter.html>.

"Gene Regulation in Eukaryotes." Eastern Michigan University. N.p.. Web. 2 Apr 2013. <http://www.emunix.emich.edu/~rwinning/genetics/eureg.htm>.

Kuwahara, K., et al. "The Neuron-Restrictive Silencer Element-Neuron-Restrictive Silencer Factor System Regulates Basal and Endothelin 1-Inducible Atrial Natriuretic Peptide Gene Expression in Ventricular Myocytes " Molecular and cellular biology 21.6 (2001): 2085-97. Print.

Maston, Glenn, Sarah Evans, and Michael Green. "Transcriptional regulatory elements in the Human Genome." Annual Reviews. Stanford University, 23 May 2006. Web. 27 Apr 2013. <http://bejerano.stanford.edu/readings/public/10_Intro_TxRegReview.pdf>.

Ogbourne, Steven, and Toni Antalis. "Transcriptional control and the role of silencers in transcriptional regulation in eukaryotes." Queensland Cancer Fund Experimental Oncology Program, The Queensland Institute of Medical Research. (1998): 1-14. Web. 27 Apr. 2013. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1219314/pdf/9512455.pdf>.

Olguin, P., et al. "RE-1 Silencer of transcription/neural Restrictive Silencer Factor Modulates Ectodermal Patterning during Xenopus Development " The Journal of neuroscience : the official journal of the Society for Neuroscience 26.10 (2006): 2820-9. Print.

Rials, Seth J. , Ying Wu, et al. "Effect of Left Ventricular Hypertrophy and Its Regression on Ventricular Electrophysiology and Vulnerability to Inducible Arrhythmia in the Feline Heart." American Heart Association. 91. (1995): 426-430. Web. 3 Apr. 2013. <http://circ.ahajournals.org/content/91/2/426.full>.

Sashida, Goro, and Atsushi Iwama. "Epigenetic regulation of hematopoiesis." International Journal of Hematology. 96.4 (2012): 405-412. Web. 27 Apr. 2013. Schoenherr, C. J., and D. J. Anderson. "The Neuron-Restrictive Silencer Factor (NRSF): A Coordinate Repressor of Multiple Neuron-Specific Genes " Science (New York, N.Y.) 267.5202 (1995): 1360-3. Print.

Walker, Francis O. . "Huntington's disease." Lancet. 369.9557 (2007): 218-228. Web. 27 Apr. 2013. <http://www.sciencedirect.com/science/article/pii/S0140673607601111>.

Zuccato, Chiara, Nikolai Belyaev, et al. "Widespread Disruption of Repressor Element-1 Silencing Transcription Factor/Neuron-Restrictive Silencer Factor Occupancy at Its Target Genes in Huntington's Disease." Journal of Neuroscience. (2007): n. page. Web. 21 Mar. 2013. <http://www.jneurosci.org/content/27/26/6972.long>

History and discovery?

To you awesome BC students: thank you for building up this article! An interesting section often seen in high-quality molecular biology Wikipedia articles is a 'History and discovery' section, which discusses things like the researcher(s) that discovered the subject, and what led them to that discovery. Examples include RNA_interference#History_and_discovery, DNA#History_of_DNA_research and Major_urinary_proteins#Discovery, Homologous_recombination#History_and_discovery and DNA_polymerase#History. This helps give context to the subject. Would it be feasible to add such a section to this article? Emw (talk) 12:51, 27 April 2013 (UTC)

• thanks so much for commenting on the student's page! They have moved on now, so the team that built up this page won't be working on it further (unless they've been seduced into continuing WP involvement, which I hope is the case!). I will be using this type of assignment in future Developmental biology courses, as well as an advanced course on pollutants that mimic hormones. DEFINITELY will include the history and discovery section in instructions to students. Helpful advice! Hakeleh (talk) 15:53, 11 May 2013 (UTC)