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#45 Jan 27, 2013
The evolution of species and the development of cancer are both Darwinian processes based on variation and selection. In our earlier analysis of the human 3p12-p22 segment, we have found a certain concordance between humanmouse synteny breaks, and tumor-associated deletions (Kiss et al. 2002; Kost-Alimova et al. 2003). Later, based on comparative sequence analysis of one tumor-related deletion at 3p21.3 (named CER1), this association has been extended to other features of evolutionary plasticity, including gene duplications, retrotranspositions, and repeated chromosome rearrangements (Darai et al. 2005). Our cancer chromosome studies were focused on the analysis of deletions, detected by the elimination test, based on the transfer of human chromosome 3 (chr 3) into mouse fibrosarcoma (A9) cells, and the subsequent identification of eliminated versus retained chr 3 segments after in vivo tumor growth (Imreh et al. 1994; Yang et al. 1999; Kholodnyuk et al. 2002; Kost-Alimova and Imreh 2007). Therefore, the question remained open as to whether the association between tumor and evolutionary breaks observed in a model system could be found in human tumors, and if the answer is affirmative, do these break-prone regions have any structural characteristics?

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#46 Jan 27, 2013
Recently, it was shown that ~5% of the human genome is composed of duplicated genomic segments, which emerged mostly during the past 35 million years of primate evolution. These segmental duplications (SDs) range from a few to hundreds of kilobases and share a high degree of sequence identity (>90%)(Eichler 2001; Samonte and Eichler 2002; Bailey and Eichler 2006). They have gone through extensive structural changes during a relatively short evolutionary time and were associated with chromosomal rearrangements in recent primate evolution (Samonte and Eichler 2002; Courseaux et al. 2003; Nahon 2003; Stankiewicz et al. 2003; Murphy et al. 2005a; Goidts et al. 2006; She et al. 2006). We decided to test whether these regions show signs of instability in human carcinoma cells, as judged by the analysis of tumor related breakpoints. Such analysis was not easy to perform earlier. Studies focused on specific sites like loss of heterozygosity (LOH) or locus-specific FISH were often biased by the choice of markers, guided by earlier studies and by the inevitable concentration on particular regions. Genome-wide studies, like karyotyping, metaphase CGH, multiplex FISH (M-FISH), or spectral karyotyping (SKY) have low resolution. In spite of these drawbacks, the earlier studies suggested a certain correspondence between evolutionary and cancer-related breakpoints. Our study showed a certain concordance between the positions of homozygous deletions at 3p12-p22 in human carcinoma lines and breaks on the mousehuman synteny maps (Kost-Alimova et al. 2003). Another human genomic region, 17p11.2-p12, is rich in SDs and is rearranged both in evolutionary and in cancer-related structural chromosome aberrations (Barbouti et al. 2004; Stankiewicz et al. 2004). Performing multispecies alignments, Murphy et al.(2005b) examined the relationship between the evolutionary and cancer-associated chromosome breakpoints using the Mitelman Database of Chromosome Aberrations in Cancer ( http://cgap.nci.nih.gov/Chromosomes/Mitelman ). They have found that frequent cancer-associated chromosome aberrations were close to evolutionary breakpoint regions three times as often as were the less frequent cancer-associated aberrations.

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#47 Jan 27, 2013
Our multipoint FISH (mpFISH) method permits the detection of chr 3 rearrangements in tumor cell lines very efficiently (Darai-Ramqvist et al. 2006). We have chosen 10 carcinoma cell lines for the analysis of breakpoints. Chr 3 is one of the most rearranged chromosomes in different human carcinomas (Kost-Alimova and Imreh 2007; Kost-Alimova et al. 2007); renal cell carcinoma, which represents a majority of our cell line samples, is one of them (van den Berg and Buys 1997; Meloni-Ehrig 2002; see also Mitelman Database of Chromosome Aberrations in Cancer). The number of rearrangements varied from three up to 68 per karyotype as detected by M-FISH. Using mpFISH we found up to 20 chr 3 breaks per cell line. We detected a total of 54 different breakpoints on chr 3 in the 10 cell lines. In the lines with high karyotype complexity they clustered at three known fragile sites, FRA3B, FRA3C, and FRA3D, and at two other regions, 3p12.3-p13 and 3q21.3-q22.1. As we show, the characterization of the last two tumor break-prone regions sheds some light on five questions we were most interested in:

1.What is the main sequence feature of the tumor break-prone regions?
2.Do tumor break-prone regions colocalize with evolutionary break-prone regions?
3.What could be the mechanism of instability within the break-prone regions?
4.How is the instability maintained during long evolutionary time?
5.What is the selective value of the instability during evolution and in cancer?

The rest, as in how they did it, i'll leave for the interested reader.

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#48 Jan 27, 2013

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#49 Jan 27, 2013
DNA METHYLATION AND GENE REGULATION
The regulation of eukaryotic gene expression is a complex process. Transcription initiation is a highly controlled and integrated event that involves cis-acting and trans-acting factors. The cis-acting elements are DNA sequences that act as the substrate for the trans-acting factors, and the DNA in the vicinity is prepared for transcription. Increased methylation in the promoter region of a gene leads to reduced expression, whereas methylation in the transcribed region has a variable effect on gene expression.23,24

Several mechanisms have been proposed to account for transcriptional repression by DNA methylation. The first mechanism involves direct interference with the binding of specific transcription factors to their recognition sites in their respective promoters. Several transcription factors, including AP-2, c-Myc/Myn, the cyclic AMP-dependent activator CREB, E2F, and NFkB, recognize sequences that contain CpG residues, and binding of each has been shown to be inhibited by methylation.1,25

The second mode of repression involves a direct binding of specific transcriptional repressors to methylated DNA. The DNA methylation signals are analyzed by the methyl-CpGbinding proteins, the target being the 5′ methylated CpG sequence.26-28 MeCP1 and MeCP2 were the first two protein complexes identified. However, several new proteins have now been identified. They include MBD1, MBD2, MBD4, and Kaiso.26 MeCP1, MBD1, MBD2, and MBD4 bind to 5mCpG through a motif called the methyl CpG binding domain (MBD). Kaiso, however, is different in mechanism, as it binds through a zinc finger motif.29 MBD4 is associated with DNA repair,26 whereas MBD1, MBD2, MeCP2, and Kaiso have been shown to repress transcription both in vitro and in cell culture assays by interacting with histone deacetylase complexes.26

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#50 Jan 27, 2013
DNA methylation can also affect histone modifications and chromatin structure, which, in turn, can alter gene expression. The underlying patterns of methylated cytosines are important in guiding histone deacetylation to certain residues.30 At present, there are five known proteins that have the methyl-CpGbinding domain, and four of these (MeCP2, MBD1, MBD2, and MBD3) are implicated in transcriptional repression.26 Three of these (MeCP2, MBD2, and MBD3) are in complexes (MeCP-2, MeCP-1 and Mi-2, respectively) that contain histone deacetylases. Studies of methylated transfected genes containing binding sites for all four of these methyl-binding proteins have shown at least partial abrogation of transcriptional repression by treatment with the histone deacetylase inhibitor, trichostatin A.

Earlier it was suggested that histone modification was secondary to DNA methylation, but recent studies on fungus revealed that histone modification can on its own commence the process of DNA methylation.31

The methylation of lysine in histones by specific histone methylases is also implicated in changes in chromatin structure and gene regulation. A zone of deacetylated histone H3 and methylation of histone H3 at lysine 9 surrounds a hypermethylated, silenced hMLH1 promoter, which, when unmethylated and active, is associated with acetylated H3 and methylation of histone H3 at lysine 4 position. Inhibiting DNA methyltransferases, but not histone deacetylases, leads initially to promoter demethylation, followed by gene re-expression, and finally to complete histone code reversal.32

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#51 Jan 27, 2013
INTRODUCTION
Epigenetics can be described as a stable alteration in gene expression potential that takes place during development and cell proliferation, without any change in gene sequence. DNA methylation is one of the most commonly occurring epigenetic events taking place in the mammalian genome. This change, though heritable, is reversible, making it a therapeutic target. Epigenetics has evolved as a rapidly developing area of research. Recent studies have shown that epigenetics plays an important role in cancer biology,1,2 viral infections,3 activity of mobile elements,4 somatic gene therapy, cloning, transgenic technologies, genomic imprinting, developmental abnormalities, mental health, and X-inactivation.5,6

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#52 Jan 27, 2013
DNA methylation is a covalent chemical modification, resulting in the addition of a methyl (CH3) group at the carbon 5 position of the cytosine ring. Even though most cytosine methylation occurs in the sequence context 5′CG3′ (also called the CpG dinucleotide), some involves CpA and CpT dinucleotides.7 DNA is made up of four bases, thus there are 16 possible dinucleotide combinations that can occur. Therefore the CpG dinucleotide should occur with a frequency of approximately 6%. However, the actual presence is only 5% to 10% of its predicted frequency.8 This CpG suppression may be related to the hypermutability of methylated cytosine. The human genome is not methylated uniformly and contains regions of unmethylated segments interspersed by methylated regions.9 In contrast to the rest of the genome, smaller regions of DNA, called CpG islands, ranging from 0.5 to 5 kb and occurring on average every 100 kb, have distinctive properties. These regions are unmethylated, GC rich (60% to 70%), have a ratio of CpG to GpC of at least 0.6, and thus do not show any suppression of the frequency of the dinucleotide CpG.10,11 Approximately half of all the genes in humans have CpG islands,8 and these are present on both housekeeping genes and genes with tissue-specific patterns of expression.1

DNA methylation is brought about by a group of enzymes known as the DNA methyltransferases (DNMT). The DNMTs known to date are DNMT1, DNMT1b, DNMT1o, DNMT1p, DNMT2, DNMT3A, DNMT3b with its isoforms, and DNMT3L.12 Methylation can be de novo (when CpG dinucleotides on both DNA strands are unmethylated) or maintenance (when CpG dinucleotides on one strand are methylated). DNMT1 has de novo as well as maintenance methyltransferase activity, and DNMT3A and DNMT3b are powerful de novo methyltransferases.4 The importance of these enzymes has been shown using several mouse experiments in which the mouse deficient in the gene dies early in development or immediately after birth.12

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#53 Jan 27, 2013
In addition to the DNMTs, the other machinery of methylation includes demethylases, methylation centers triggering DNA methylation, and methylation protection centers.4,13 DNA methylation patterns are established early in embryogenesis and are very finely controlled during development. The enzymes that actively demethylate DNA include 5-methylcytosine glycosylase, which removes the methylated cytosine from DNA, leaving the deoxyribose intact14 (eventually local DNA repair adds back the cytosine in nucleotide form), and MBD2b, which refers to an isoform that results from initiation of translation at the second methionine codon of the gene encoding methyl-CpG binding domain 2 (MBD2) protein.15 MBD2b lacks glycosylase or nuclease activity and is thought to cause demethylation by hydrolyzing 5-methylcytosine to cytosine and methanol. However, two independent laboratories have not been able to reproduce these results in mammalian and Xenopus systems.16,17

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#54 Jan 27, 2013
Earlier it was thought that normal cells become progressively transformed to malignant cells as a consequence of damage to the genome, which could be a gain, loss, or mutation of the genetic information. These events cause critical loss of gene activity and thereby predispose to cancer. DNA methylation can modify the gene activity without changing the gene sequence and has been proposed as one of the two hits in Knudson's two hits hypothesis for oncogenic transformation.18 Methylation changes have been implicated in tumorigenesis. Genetic disruption of both DNMT1 and DNMT3b in a colorectal cell line reduced DNA methylation and resulted in the loss of insulin-like growth factor II imprinting, abrogation of silencing of the tumor suppressor gene p16INK4a, and growth suppression.19 Multiple intestinal neoplasia mice carry a germ-line mutation in the murine adenomatous polyposis coli (Apc) ortholog and are predisposed to the development of intestinal neoplasia. The combined effects of heterozygosity for a null mutation of the Dnmt1 gene and treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidi ne could reduce polyp multiplicity in ApcMin/+ mice.20 Mice deficient in MLH1 (one of the mismatch repair proteins) carrying the hypomorphic Dnmt1 mutation have a reduced incidence of adenomas, whereas the risk of lymphoma in these mice is increased.21 A less severe disruption of Dnmt1 expression in mice carrying a hypomorphic DNA methyltransferase 1 (Dnmt1) allele reduced Dnmt1 expression to 10% of wild-type levels. This resulted in substantial genome-wide hypomethylation in all tissues, and these mice developed aggressive T-cell lymphomas that displayed a high frequency of chromosome 15 trisomy.22 Therefore, genomic demethylation may protect against some cancers, such as intestinal tumors in the ApcMin mouse model, but may promote genomic instability and loss of heterozygosity and increase the risk of cancer in other tissues, as seen in hypomethylated mutant mice.

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#55 Jan 29, 2013
Punctuated equilibria, particularly adjustments to the theory.
https://docs.google.com/viewer...

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#56 Jan 29, 2013
Careful measurements of morphological variation in successive fossil populations

typically reveal complex shifts in virtually all continuously variable parameters (such as overall body size and

overall body shape; Fig. 3a and c). In addition, local rates of morphological change are known to be inversely

scale-dependent (the smaller the time interval between successive samples, the greater the rate). Such

patterns are presumably driven by a combination of genuine response to local environmental change, genetic

drift, the effect of migration and emigration, and sampling error. The attribution of stasis is applied when

these data appear directionless, or at least statistically indistinguishable from a random pattern.

Do such patterns provide evidence for the operation of species-specific constraints on morphological

evolution? Although genetic phenomena such as pleiotropy (a condition in which multiple morphological

effects are produced by variation in a single gene) and canalization (a condition in which the expression of a

gene complex is constrained to occur along discrete pathways leading to a specific range of morphological

types irrespective of changes in environmental conditions) are well known, Gould and Eldredge's early

writings are vague about the precise manner in which such phenomenawhich themselves can be selected

for or againstrepresent species-defining characteristics or how such factors might operate in an

evolutionary context. Moreover, as pointed out by Richard Dawkins, evidence from laboratory populations is

not encouraging. If such constraints were present, artificial selection experiments should detect their

presence. Instead, the common observation is that laboratory populations seem almost infinitely malleable

for continuous characteristics until such time as a lack of variation due to inbreeding (reflecting a lack of time

for mutation to occur) terminates the experiment.

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#57 Jan 29, 2013
Resolution of dilemma

A resolution to the dilemma posed by punctuated equilibria's stasis mode was proposed in 1987 by Douglas

Futuyama, and is now receiving increased attention from paleontologists as a result of its acceptance by

Gould and Eldredge. Futuyama argues that the morphological stasis pointed to by Gould and Eldredge is

exactly what it appears to be: a collection of directionless and temporary responses to local environmental

change on the part of a large, heterogeneous population which, through time, becomes statistically

overwhelmed by recombination coupled with stabilizing selection. The only way for lineages to surmount

long-term stasis and preserve any component of localized adaptation, according to Futuyama's model, is

through an allopatric speciation event, in which case back-crossing with the parent population is prevented.

Futuyama's model provides a compelling resolution to the original controversy by its abandonment of

attributions to ill-defined and experimentally unsupported organizational constraints, and by its shifting of the

focus of the explanation for stasis back to the speciation event itself, which was always felt by all parties to

fall squarely within the Neo-Darwinian paradigm.

See also: Organic evolution; Paleontology; Population genetics; Speciation

R. Dawkins, The Blind Watchmaker, W. W. Norton, New York, 1986

D. J. Futuyma, On the role of species in anagenesis, Amer. Naturalist, 130:465473, 1987

S. J. Gould, The Structure of Evolutionary Theory, Belknap/Harvard University Press, Cambridge, 2002

S. J. Gould and N. Eldredge, Punctuated equilibria: An alternative to phyletic gradualism, in T. J. M.

Schopf (ed.), Models in Paleobiology, pp. 82115, Freeman, Cooper, San Francisco, 1972

S. J. Gould and N. Eldredge, Punctuated equilibria: The tempo and mode of evolution reconsidered,

Paleobiology, 3:115151, 1977

S. J. Gould and N. Eldredge, Punctuated equilibrium comes of age, Nature, 366:223227, 1993

http://www.accessscience.com/popup.aspx...

McGraw-Hill's AccessScience

A. H. Cheetham, Tempo of evolution in a Neogene bryozoan: Rates of morphologic change within and

across species boundaries, Paleobiology, 12:190202, 1986

S. J. Gould and R. C. Lewontin, The spandrels of San Marco and the Panglossian paradigm: A critique of

the adaptationist programme, Proc. Roy. Soc. London, Ser. B, 205:581598, 1979

D. E. Kellogg, The role of phyletic change in the evolution of Pseudocubus vema (Radiolaria),

Paleobiology, 1:359370, 1975

T. Ozawa, Evolution of Lepidolina multiseptata (Permian foraminifer) in East Asia, Mem. Faculty Sci.

Kyushu Univ., Ser. D (Geology), 23:117164, 1975

How to cite this article

Norman MacLeod, "Punctuated equilibria (evolutionary theory)", in AccessScience@McGraw-Hill,

http://www.accessscience.com , DOI 10.1036/1097-8542.YB040445

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#58 Jan 29, 2013
A 1960 article. sugars and methylation (preserving f.i. the antigen in bloodgroups)
https://docs.google.com/viewer...

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#59 Jan 29, 2013
Carbohydrates and Glycobiology. chapter 7

(d) Results 1 and 2. Result 1 is consistent with the known structure, because type B antigen
has three molecules of galactose; types A and O each have only two. Result 2 is also con-
sistent, because type A has two amino sugars (N-acetylgalactosamine and N-acetylglu-
cosamine); types B and O have only one (N-acetylglucosamine). Result 3 is not consistent
with the known structure: for type A, the glucosamine:galactosamine ratio is 1:1; for type
B, it is 1:0.
(e) The samples were probably impure and/or partly degraded. The first two results were
correct possibly because the method was only roughly quantitative and thus not as sensi-
tive to inaccuracies in measurement. The third result is more quantitative and thus more
likely to differ from predicted values, because of impure or degraded samples.
(f) An exoglycosidase. If it were an endoglycosidase, one of the products of its action on O
antigen would include galactose, N-acetylglucosamine, or N-acetylgalactosamine, and at
least one of those sugars would be able to inhibit the degradation. Given that the enzyme
is not inhibited by any of these sugars, it must be an exoglycosidase, removing only the
terminal sugar from the chain. The terminal sugar of O antigen is fucose, so fucose is the
only sugar that could inhibit the degradation of O antigen.
(g) The exoglycosidase removes N-acetylgalactosamine from A antigen and galactose from B
antigen. Because fucose is not a product of either reaction, it will not prevent removal of
these sugars, and the resulting substances will no longer be active as A or B antigen.
However, the products should be active as O antigen, because degradation stops at fucose.
(h) All the results are consistent with Figure 1015.(1) D-Fucose and L-galactose, which
would protect against degradation, are not present in any of the antigens.(2) The termi-
nal sugar of A antigen is N-acetylgalactosamine, and this sugar alone protects this antigen
from degradation.(3) The terminal sugar of B antigen is galactose, which is the only
sugar capable of protecting this antigen.

Morgan, W.T.(1960) The Croonian Lecture: a contribution to human biochemical genetics; the chemical basis of blood-group specifici-
ty. Proc. R. Soc. Lond. B Biol. Sci. 151, 308347.

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#60 Jan 29, 2013
http://www.nature.com/scitable/topicpage/the-...

The role of methylation in gene-expression (mind not histione methylation) particularly in epigenetic processes...switch-off.

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#61 Jan 29, 2013
The Role of Methylation in Gene Expression
By: Theresa Phillips, Ph.D.(Write Science Right) 2008 Nature Education Citation: Phillips, T.(2008) The role of methylation in gene expression. Nature Education 1(1)
.Not all genes are active at all times. DNA methylation is one of several epigenetic mechanisms that cells use to control gene expression.
1Introduction.25-azacytidine Experiments Provide Early Clues to the Role of Methylation in Gene Expression .3How and Where Are Genes Methylated?.4The Role of Methylation in Gene Expression .5DNA Methylation and Histones .6DNA Methylation and Disease .7Summary .8References and Recommended Reading.


There are many ways that gene expression is controlled in eukaryotes, but methylation of DNA (not to be confused with histone methylation) is a common epigenetic signaling tool that cells use to lock genes in the "off" position. In recent decades, researchers have learned a great deal about DNA methylation, including how it occurs and where it occurs, and they have also discovered that methylation is an important component in numerous cellular processes, including embryonic development, genomic imprinting, X-chromosome inactivation, and preservation of chromosome stability. Given the many processes in which methylation plays a part, it is perhaps not surprising that researchers have also linked errors in methylation to a variety of devastating consequences, including several human diseases.
5-azacytidine Experiments Provide Early Clues to the Role of Methylation in Gene Expression

Prior to 1980, there were a number of clues that suggested that methylation might play a role in the regulation of gene expression. For example, J. D. McGhee and G. D. Ginder compared the methylation status of the beta-globin locus in cells that did and did not express this gene. Using restriction enzymes that distinguished between methylated and unmethylated DNA, the duo showed that the beta-globin locus was essentially unmethylated in cells that expressed beta-globin but methylated in other cell types (McGhee & Ginder, 1979). This and other evidence of the time were indirect suggestions that methylation was somehow involved in gene expression.

Shortly after McGhee and Ginder published their results, a more direct experiment that examined the effects of inhibiting methylation on gene expression was performed using 5-azacytidine in mouse cells. 5-azacytidine is one of many chemical analogs for the nucleoside cytidine. When these analogs are integrated into growing DNA strands, some, including 5-azacytidine, severely inhibit the action of the DNA methyltransferase enzymes that normally methylate DNA.(Interestingly, other analogs, like Ara-C, do not negatively impact methylation.) Because most DNA methylation was known to occur on cytosine residues, scientists hypothesized that if they inhibited methylation by flooding cellular DNA with 5-azacytidine, then they could compare cells before and after treatment to see what impact the loss of methylation had on gene expression. Knowing that gene expression changes are responsible for cellular differentiation, these researchers used changes in cellular phenotypes as a proxy for gene expression changes (Table 1; Jones & Taylor, 1980).

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How and Where Are Genes Methylated?
Today, researchers know that DNA methylation occurs at the cytosine bases of eukaryotic DNA, which are converted to 5-methylcytosine by DNA methyltransferase (DNMT) enzymes. The altered cytosine residues are usually immediately adjacent to a guanine nucleotide, resulting in two methylated cytosine residues sitting diagonally to each other on opposing DNA strands. Different members of the DNMT family of enzymes act either as de novo DNMTs, putting the initial pattern of methyl groups in place on a DNA sequence, or as maintenance DNMTs, copying the methylation from an existing DNA strand to its new partner after replication. Methylation can be observed by staining cells with an immunofluorescently labeled antibody for 5-methylcytosine. In mammals, methylation is found sparsely but globally, distributed in definite CpG sequences throughout the entire genome, with the exception of CpG islands, or certain stretches (approximately 1 kilobase in length) where high CpG contents are found. The methylation of these sequences can lead to inappropriate gene silencing, such as the silencing of tumor suppressor genes in cancer cells.

Currently, the mechanism by which de novo DNMT enzymes are directed to the sites that they are meant to silence is not well understood. However, researchers have determined that some of these DNMTs are part of chromatin-remodeling complexes and serve to complete the remodeling process by performing on-the-spot DNA methylation to lock the closed shape of the chromatin in place.

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#63 Jan 29, 2013
The roles and targets of DNA methylation vary among the kingdoms of organisms. As previously noted, among Animalia, mammals tend to have fairly globally distributed CpG methylation patterns. On the other hand, invertebrate animals generally have a "mosaic" pattern of methylation, where regions of heavily methylated DNA are interspersed with nonmethylated regions. The global pattern of methylation in mammals makes it difficult to determine whether methylation is targeted to certain gene sequences or is a default state, but the CpG islands tend to be near transcription start sites, indicating that there is a recognition system in place.

Plantae are the most highly methylated eukaryotes, with up to 50% of their cytosine residues exhibiting methylation. Interestingly, in Fungi, only repetitive DNA sequences are methylated, and in some species, methylation is absent altogether, or it occurs on the DNA of transposable elements in the genome. The mechanism by which the transposons are recognized and methylated appears to involve small interfering RNA (siRNA). The whole silencing mechanism invoking DNMTs could be a way for these organisms to defend themselves against viral infections, which could generate transposon-like sequences. Such sequences can do less harm to the organism if they are prevented from being expressed, although replicating them can still be a burden (Suzuki & Bird, 2008). In other fungi, such as fission yeast, siRNA is involved in gene silencing, but the targets include structural sequences of the chromosomes, such as the centromeric DNA and the telomeric repeats at the chromosome ends.

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The Role of Methylation in Gene Expression

For many years, methylation was believed to play a crucial role in repressing gene expression, perhaps by blocking the promoters at which activating transcription factors should bind. Presently, the exact role of methylation in gene expression is unknown, but it appears that proper DNA methylation is essential for cell differentiation and embryonic development. Moreover, in some cases, methylation has observed to play a role in mediating gene expression. Evidence of this has been found in studies that show that methylation near gene promoters varies considerably depending on cell type, with more methylation of promoters correlating with low or no transcription (Suzuki & Bird, 2008). Also, while overall methylation levels and completeness of methylation of particular promoters are similar in individual humans, there are significant differences in overall and specific methylation levels between different tissue types and between normal cells and cancer cells from the same tissue.

Researchers have also determined that mice that lack a particular DNMT have reduced methylation levels and die early in development (Suzuki & Bird, 2008). This is not the case for all eukaryotes, however; some organisms, such as the yeast Saccharomyces cerevisiae and the nematode worm Caenorhabditis elegans, are thought to have no methylated DNA at all (although, at least in yeast, there are sequences in their genomes that are homologous to those that code for the DNMT enzymes).

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