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(Genetics) Is a silencer the same as gene silencing (heterochromatin)?

(Genetics) Is a silencer the same as gene silencing (heterochromatin)?



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Is silencer the same as gene silencing? I know that gene silencing refers to those heterochromatin concentrated at the telomeres or centromere. It is also related to methylation. But what about a silencer. Are they the same? Or is silencer an opposite of enhancer (repressor)?


You are a bit confused with your terms here. Remember, when you are talking about natural regulation of a transcriptome, you can control it at the level of the genome, transcriptome and the epigenome.

The Repressor protein is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. Depending on where it binds, it regulates at the level of the genome or transcriptome.

The Gene Silencer Region, is a DNA sequence in the geneome that that allows repressor proteins to bind to it. It is usually very near the promoter of the gene that it wants to control. This controls the expression of the gene at the level of the genome to repress the transcription of the gene. There exists a few types (Classc silencers, negative regulators and polycomb response) but lets not get into that).

An example is the regulatory element in the classical Lac operon.

Gene Silencing as you call it is epigenetic in nature. I'll point you towards the wiki as it is quite big and diverse to explain it here: http://en.wikipedia.org/wiki/Gene_silencing

you can read more about it here:http://www.ncbi.nlm.nih.gov/books/NBK26872/


Heterochromatin silencing of p53 target genes by a small viral protein

The transcription factor p53 (also known as TP53) guards against tumour and virus replication and is inactivated in almost all cancers. p53-activated transcription of target genes is thought to be synonymous with the stabilization of p53 in response to oncogenes and DNA damage. During adenovirus replication, the degradation of p53 by E1B-55k is considered essential for p53 inactivation, and is the basis for p53-selective viral cancer therapies. Here we reveal a dominant epigenetic mechanism that silences p53-activated transcription, irrespective of p53 phosphorylation and stabilization. We show that another adenoviral protein, E4-ORF3, inactivates p53 independently of E1B-55k by forming a nuclear structure that induces de novo H3K9me3 heterochromatin formation at p53 target promoters, preventing p53–DNA binding. This suppressive nuclear web is highly selective in silencing p53 promoters and operates in the backdrop of global transcriptional changes that drive oncogenic replication. These findings are important for understanding how high levels of wild-type p53 might also be inactivated in cancer as well as the mechanisms that induce aberrant epigenetic silencing of tumour-suppressor loci. Our study changes the longstanding definition of how p53 is inactivated in adenovirus infection and provides key insights that could enable the development of true p53-selective oncolytic viral therapies.


Abstract

Recent transcriptome analyses show that substantial proportions of eukaryotic genomes can be copied into RNAs, many of which do not encode protein sequences. However, cells have developed mechanisms to control and counteract the high transcriptional activity of RNA polymerases in order to achieve cell-specific gene activity or to prevent the expression of deleterious sequences. Here we compare how two silencing modes — the Polycomb system and heterochromatin — are targeted, established and maintained at different chromosomal locations and how DNA-binding proteins and non-coding RNAs connect these epigenetically stable and heritable structures to the sequence information of the DNA.


MATERIALS AND METHODS

Plasmids and yeast strains:

Plasmids used in this study are listed in Table 1. The LEU2 gene in plasmids pYC318 through 348 was replaced by the TRP1 gene to make pXZ22 through pXZ25, respectively. Plasmid pXZ26 was similarly derived from pMS358. pH3-H4 is a CEN-TRP1-based plasmid carrying the HHT2-HHF2 cassette. Plasmid pH3-H4-K16Q is identical to pH3-H4 except carrying an hhf2 allele encoding H4-K16Q. The other plasmids carrying H3 or H4 single mutant alleles are similar named, but not listed in Table 1.


Conversion of a gene-specific repressor to a regional silencer

In Saccharomyces cerevisiae, gene silencing at the HMR and HML loci is normally dependent on Sir2p, Sir3p, and Sir4p, which are structural components of silenced chromatin. Sir2p is a NAD+-dependent histone deacetylase required for silencing. Silencing can be restored in cells lacking Sir proteins by a dominant mutation in SUM1, which normally acts as a mitotic repressor of meiotic genes. This study found that mutant Sum1-1p, but not wild-type Sum1p, associated directly with HM loci. The origin recognition complex (ORC) was required for Sum1-1p-mediated silencing, and mutations in ORC genes reduced association of Sum1-1p with the HM loci. Sum1-1p-mediated silencing also depended on HST1, a paralog of SIR2. Both Sum1-1p and wild-type Sum1p interacted with Hst1p in coimmunoprecipitation experiments. Therefore, the SUM1-1 mutation did not change the affinity of Sum1p for Hst1p, but rather relocalized Sum1p to the HM loci. Sum1-1-Hst1p action led to hypoacetylation of the nucleosomes at HM loci. Thus, Sum1-1p and Hst1p could substitute for Sir proteins to achieve silencing through formation of a compositionally distinct type of heterochromatin.

Figures

Sum1-1p associated with HM loci.…

Sum1-1p associated with HM loci. ( A ) Lysates were prepared from formaldehyde…

Wild-type Sum1p did not associate…

Wild-type Sum1p did not associate with HM loci. ( A ) Chromatin immunoprecipitation…

ORC was required for Sum1-1p-mediated…

ORC was required for Sum1-1p-mediated silencing. ( A ) MAT α haploids of…

ORC was required for Sum1-1p…

ORC was required for Sum1-1p association with HM loci. ( A ) MAT…

Hst1p was in complexes with…

Hst1p was in complexes with both Sum1-1p and wild-type Sum1p. ( A )…

Sum1-1p-mediated silencing was associated with…

Sum1-1p-mediated silencing was associated with histone deacetylation. Chromatin immunoprecipitations used MAT α haploids…


Applications of gene silencing:

Gene silencing has a tremendous role in genetic engineering and transgenic construction . In the plant genetics various economically important plants can be constructed using the present method.

In the medical field, the gene silencing technique is used to study genes associated with cancer, infectious disorders and other genetic disorders .

As we said, overexpression of some genes causes cancer, which is silenced by the shRNA and miRNA mediated technique.

The gene silencing is also used in plant genetics for creating genetically modified organisms or plants that are economically important.

The siRNA mediated gene silencing is used in treating infectious diseases like HIV. Here the viral RNA gene is targeted using the siRNA which binds to it and makes it inactive transcriptionally.

This technique is now under the trial phase for HIV and hepatitis infection, although results are unambiguous.

Scientists are now applying the gene silencing method to treat diseases like asthma, cystic fibrosis , chronic obstructive pulmonary disease, hepatitis B, hepatitis C, chronic myeloid leukemia and neurodegenerative disorders.

Genetically engineered plant species that produce less toxin are now constructed using the present RNA interference technique.

It is used in agribiotechnology, microbiology, food processing technology and in other science fields for various applications.


Gene silencing and cancer

RNAi has been used to silence genes that are associated with several forms of cancer. Cancer comes in many forms, but there are a number of universal aberrations common to all cancers. One of these is the epigenetic silencing of tumor suppressor genes (TSGs).

The silencing of TSGs is believed to be an early, driving event in the development of cancer in humans.

As a result, efforts have been made to develop small molecules aimed at the restoration of TSGs to limit tumor cell proliferation and survival.

Recent evidence indicates that epigenetic changes might 'addict' cancer cells to altered pathways during the early stages of tumor development. Dependence on these pathways for cells to grow or survival allows them to acquire genetic mutations in the same pathways, providing the cell with characteristics that promote tumor progression.

Strategies to reverse epigenetic gene silencing could be useful in cancer prevention and therapy.

As an example, chemokine receptor chemokine receptor 4 (CXCR4), associated with the proliferation of breast cancer, was cleaved by siRNA molecules that reduced the number of divisions commonly observed by the cancer cells. Researchers have also used siRNAs to selectively regulate the expression of cancer-related genes.

Studies are also being increasingly utilized to study the potential use of siRNA molecules in cancer therapeutics. For instance, mice implanted with colon adenocarcinoma cells were found to survive longer when the cells were pretreated with siRNAs that targeted B-catenin in the cancer cells.


Materials and Methods

Plasmids and Strains.

The plasmids described below were constructed by inserting a sequence of chromosome III into the polylinker of pUC19. Plasmid pUC26 contains the BamHI–HMLBamHI fragment corresponding to region 9666–16263 of chromosome III (base pair coordinates are from the complete sequence of chromosome III). The HpaI–HML I–HindIII (14561–14838) fragment in plasmid pUC26 was inverted to make plasmid pXB87. Plasmids pMB35, pAR61, pMB11, pMB10, and pDM33 contain the HindIII–HindIII (13679–14838), HindIII–BamHI (14838–16263), EcoRI–HindIII (14838–16713), HindIII–HindIII (17021–18961), and XbaI–XbaI (10838–12015) fragments, respectively. The HpaI–HML I–HindIII fragment (14561–14838) was inserted at HpaI site of pDM33 in both orientations to yield plasmids pGJ51 and pGJ52. The 1.1-kb BglII–URA3BglII fragment of plasmid pFL44 (14) was used in constructing a series of plasmids for the insertion of URA3 at different sites within or near the HML locus on chromosome III. URA3 was inserted at the PvuII site of pMB35 in both orientations to make plasmids pMB36 and pMB37, at SnaBI of pAR61 to make plasmids pMB16a and -b, at the EcoRV site of pAR61 to generate plasmids pMB22a and -b, at the BamHI site of pMB11 to make plasmids pMB13a and -b, and at the BglII site of pMB10 to make plasmids pMB12a and -b. Plasmid pGJ8 contains the EcoRI–HindIII (11294–14838) fragment of chromosome III in which the XbaI–XbaI (12015–12535) fragment was replaced by URA3. Plasmid pMB21 consists of pRS404 (15) into which the SIR3 and SUP4-o genes have been inserted at the SacI + BamHI and BamHI sites, respectively. Plasmids pXB68, pXB69, pXB70, and pXB71 contain PCR fragments from chromosome III positions 9658–11158 (designated α, Fig. 4A) 14701–16201 (β) 289,776–291,276 (γ) and 293,628–295,128 (δ), respectively, inserted at the SpeI site of pYXB26 (11).

Strain Y851 is mata1 HMLα HMRα leu2–3,112 trp1Δ ade8 ura3–52, and strain Y1423 is identical to strain Y851 except for inactivation of SIR3 by insertion of LEU2. All other strains used in this study were derived from strain DMY1 (MATa ura3–52 leu2–3,112 ade2–1 lys1–1 his5–2 can1–100 ref. 16). Strain YXB76 was made by transforming strain DMY20 (DMY1, ΔESUP4-o-HMLα-ΔI ref. 16) to canavanine-resistance with the BamHI–E–HMLα–I(inverted)–BamHI fragment of plasmid pXB87. Strain YXB77 was derived from strain YXB76 by disrupting SIR3 with LEU2 as described (16). Strain Y1861s was constructed by transforming strain DMY2 (DMY1, sir3LEU2 ref. 16) to Ura + with EcoRI plus HindIII-digested pGJ8 DNA. Strains Y1995s, Y1996s, YXB78-Is, YXB78-IIs, YXB79-Is, YXB79-IIs, YXB80-Is, YXB80-IIs, and YXB81s were similarly derived from DMY2 by transformation with appropriately digested pMB36, pMB37, pMB16a, pMB16b, pMB22a, pMB22b, pMB13a, pMB13b, and pMB12a DNAs, respectively. These strains were rendered SIR3 + by integrating pMB21 at TRP1 in the genome, resulting in the strains listed in Fig. 1B. All the strains listed in Fig. 5A were obtained by first transforming strain YXB77 to Ura + with the plasmids listed above and then converting the resulting transformants to SIR3 + by integrating pMB21 at TRP1 in the genome. Strains YXB68 to YXB71 were made by transforming strain Y2047b (DMY1, ΔESUP4-o-HMLα-ΔI LEU2-GAL10-FLP1 [cir 0 ] ref. 17) to canavanine-resistance with BamHI-digested plasmid pXB68 to pXB71, respectively. Strain DMY19s (DMY1, ΔESUP4-o-HMLα-ΔI sir3LEU2) was transformed to canavanine-resistance by using XbaI-digested pGJ51 or pGJ52 to yield strains GJY75s and GJY77s, which were transformed with pMB21 to yield strains GJY75 and GJY77. Strain YXB100 is DMY1, E-HMLα-ΔI sir3LEU2 SIR3-SUP4-o. All strain constructions were confirmed by Southern blot analysis.

Chromatin Immunoprecipitation.

Chromatin immunoprecipitation assays were performed as described previously (18).


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We thank T. Andresson and M. O’Neill for mass spectrometry analyses. We also thank J. Barrowman for editing the manuscript, H.D. Folco, M. Zofall, Y. Wei, H. Xiao, and members of the S.I.S.G. laboratory for technical assistance and helpful discussions and R. Allshire for strains. This study used the Helix Systems and Biowulf Linux cluster at the NIH. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute.

↵ 1 Present address: Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.


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