User:Richjoo/Silencers Project Proposal

Tara Sung, Richard Joo, Chris Lucaj BI432 Wikipedia Project: Proposal Topic: Silencers

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. Silencers are DNA sequences that are found in both eukaryotes and prokaryotes that are capable of binding transcription regulation factors called repressors. When repressors are bound to the silencers, RNA polymerase is prevented from allowing transcription and will decrease or fully suppress RNA synthesis. If transcription is prevented, proteins will not be translated from the RNA. Because silencers are so important to the accessibility of organisms to proteins, it is important to explain the purpose, functionality, diversity, and evolution of silencers. The best way to delve into this is to show the differences of silencers and functions across eukaryotes and prokaryotes. Comparing the different types of silencers and the genes they prevent the transcription of across both closely related and distantly related organisms would also show the evolution and diversity of silencers. Mutations in Silencer and Transcription Factors that cause diseases and abnormalitites. We will also be talking about the exact mechanism that the silencers undergo during the repression of an expressed gene. Also, we will go into detail the bonding of the repressor proteins to the silencer and the creation of heterochromatin. This then makes the gene inaccessible to transcriptional proteins.

1.	Huntington’s disease Huntington’s disease results from a mutation in the huntington protein. A wild-type huntingtin protein inhibits the activity of NRSE (neural restrictive silencer element), which allows the increased transcription of BDNF. By having a mutation in this protein, NRSE-containing genes lose expression and alter the neuronal phenotype of organisms. In summary, Huntington’s disease develops when the control in the availability of REST/NRSF to NRSE is lost. Sources: http://www.ncbi.nlm.nih.gov/pubmed/12881722 http://www.medicine.virginia.edu/basic-science/departments/neurosci/neurodiseasesjournclub/Zuccato-et-al-Huntingtin-interacts.pdf

2.	REST/NRSF (transcription factor that binds with RE1/NRSE silencer)mutation a.	A study made with mice presented that a mutation in the REST/NRSF and its consequent absence, resulted in the excessive expression of βIII tubulin gene. The lack of silencing in the gene led to morphological alterations “in the head mesenchyme and somites.” Furthermore, these modifications led to the death of the embryos. This shows that REST/NRSF have a role in regulating normal development and also in the expression of neuronal genes. b.	In Xenopus laevis, the mutation in the REST/NRSF presented abnormal eye development and perturbation in neural tube and cranial ganglia. These mutations were mainly due to an altering in the process of gastrulation. Moreover, if REST/NRSF functions are altered during late blastula stage, the neural plates expand, and the epidermal keratin and neural crest markers decrease in expression. Finally, modification in the function of REST/NRSF leads to deficiencies in neural cell development due to alterations in the expression of neuronal genes. Sources: http://www.jneurosci.org/content/26/10/2820.full.pdf+html

http://www.ncbi.nlm.nih.gov/pubmed/16525062?dopt=Abstract&holding=npg c.	NRSF also affects ventricular hypertrophy, which is the thickening of the ventricular walls. This is mostly due to the synthesis of atrial natriuretic peptide (ANP). Since NRSF controls the repression of the genes that synthesize this protein, a mutation in NRSF causes the overexpression of this protein, and causes this condition. NRSE is also involved in this process acting as a mediator that represses ANP promoter sites. Sources: http://www.ncbi.nlm.nih.gov/pubmed/11238943?dopt=Abstract&holding=npg

Additional sources for future use:

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

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

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

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

(important one) http://www.ncbi.nlm.nih.gov/books/NBK7588/ http://www.ncbi.nlm.nih.gov/books/NBK10023/ http://www.ncbi.nlm.nih.gov/pubmed/23198762