Received 15th September 2004
accepted on 23 March 2005 Published
23rd March 2005
2005 and Chen Zhao; dismissed Ltd.This BioMed Central Open Access is an item under the terms of the Creative Commons license (http://creativecommons.org/licenses/by / 2.0), Who approved l & amp , 39; unrestricted use, distribution and reproduction in any medium, provided the & 39; work is properly cited.
Outline Summary Summary Background
method results discussion conclusion of the authors of contributions thanks Background Notes
It was a puzzle the long term, if the chromatin can be further divided into different areas d & 39; gene. Since deacetylation of histones affect the structure of chromatin, which in turn also affect the & 39; gene in the vicinity of the deacetylation of histones sites can be in the partition chromatin & 39; of gene expression in different areas. In this article, we examine the relationship between the locations and deacetylation of histones gene expression patterns in the genome level with a variety of data sources, in particular the measurement data microarray gene expression levels, the data in a position to microarray deacetylation of histones sites, information on the objectives of transcription factors. The result with 269 Saccharomyces cerevisiae Kleinstnetzen data, the deacetylation of histones of data, and the regulation of the goals of factors, from the transcription & 39; together Yeast Proteome Database and ChIP-chip database, we have found that sites deacetylation of histones, the co-expression of genes neighbors. Conclusion histone deacetylation sites can be considered as locations for the partition and chromatin areas l & 39; gene.
Outline background
Summary Background Method Results Discussion conclusion of the authors of contributions thanks Notes
It is known that & 39; of Histone acetylation and deacetylation are involved in the transcription. Firstly, the changes in histones can l & 39; affinity of Histone proteins from DNA sequences d & 39;. The folding top disrupted order chromatin, which in turn can affect the process of transcription [1.2], because the chromosome structural changes can have significant impact on the accessibility of & 39; of transcription factors to their target sequences [ 3.4]. Secondly, certain websites from lysine ac tyl e Histone proteins can be used as the plasma protein binding of bertragungfaktoren [5-7]. D sac tylation of histones is also associated with the stability of & 39; man in the expression of genes & 39; cancer. For example, in the cancer cells, cycline-dependent kinase inhibitor p21WAF1 is silenced by the developer histone hypoacetylation recruited by histones d ac tylases [8.9]. P21WAF1 is seen as a good faith gene, the tumor, and its activity can be restored by inhibitors d & 39; histone d sac tylase, in connection with the histone & 39; sponsor hyperacetylation [9] . Therefore, there is a lot of interest and the potential for the study and & 39; l & 39; Histone acetylation of deacetylation. L & 39; organization of chromatin can be divided into two sections: l & 39; heterochromatin and & 39; euchromatine. The transfer of genes in the genome is usually suppressed & 39; euchromatine during the genes are usually active. Recent studies have shown that the boundaries of & 39; heterochromatin are surrounded by high l & 39; acetylation of histones [10]. It was a patience game, when long-term chromatin even in areas of gene & 39; separately, with the reports showing that the co-expressed genes are in the areas of chromatin [11-14], which suggests that & 39; euchromatine possibly still in separate areas. Experience has shown that the evolution of genes & 39; can cause abnormal positions, the regulation of genes, which also & 39; support of this hypothesis [15.16]. Recent studies on the borders and the insulators also suggest that chromatin can be partitioned, in the & 39; of the gene among areas on the basis of the borders and of the insulating effects of proximity or close & by l; 39; heterochromatin and [17.18]. Therefore, the genes in the areas of blocks can be co-regulated by unknown mechanisms. For example, chicken HS4 -globin is an isolation in the region of chromatin with transitions & 39, and the acetylation of histones levels: the regions of the chromatin quietly with hypoacetylated and Lys-9 methylated histones of active chromatin region with ac tyl es Histone and actively in the genes Erythroid cells [10]. It is known that & 39; there is a correlation between the level of & 39; acetylation of histones and the & 39; gene [19]. But the details of the relationship between & 39; acetylation of histones and gene expression patterns areas is less clear. Hypoacetylated histones in chromatin are silent. Histone hyperacetylation can folding nucleosomal arrays of structures in the more condensed chromatin [1.2]. Conversely, the deacetylation of histones to stabilize higher chromatin bending. We have the hypothesis that & 39; l & 39; of Histone acetylation sites can serve & 39; boundaries of the gene areas. Although the genes neighbours tend to co-regulated and by some, because of their proximity, d & 39; higher order by deacetylation chromatin folding bed histones can reduce the impact of neighbourhood, preventing and the distal L & ; amp; 39; access to the promoter.
Outline Results Summary Background
methods results discussion conclusion of the authors of contributions thanks Notes
Figures
Figure 1Scatter plot for the newspaper of distances and physical & 39; correlations of the expression of genes without neighbors deacetylation site
Figure plot for 2Scatter , the newspaper of the distances and physical & 39; gene correlations with neighbours deacetylation A website
Figure 3Comparison empirical cumulative distributions of the two samples
Figure 4Le histograms for the p-values for the correlations in the partition groups
Tables
Table 1The hypergeometric test for the effect & 39; Co-expression of genes with the neighbors. For each threshold correlation, the number of pairs of correlations for the adjacent genes, which is above the threshold has been counted. The probability of randomly drawing a large number of these pairs of genes that are on the threshold of the & 39; all pairs of genes is a hypergeometric distribution, as the p-values.
Table 2The hypergeometric test for the effect of the partition deacetylation websites. For each threshold correlation, the number of pairs of correlations for the neighboring genes separated by deacetylation sites that are above the threshold has been counted. The probability of randomly drawing a small number of these pairs of genes on the threshold of & 39; all pairs of adjacent genes is supported by a hypergeometric distribution.
Table 3La hypergeometric tests to follow the division of the deacetylation of the sites for the co-regulated (YPD) pairs of genes. For each threshold correlation, the number of pairs of genes correlations with a regulatory authority and municipality in the same partition Group, which was on the threshold counted. The number of pairs of correlations for the same genes with regulators, and in the neighboring groups times greater than the threshold value was also counted. The probability of randomly drawing a large number of these pairs of genes that are on the threshold of the & 39; all pairs of the same gene regulator is a hypergeometric distribution. The p-values are in the table.
Table 4Le hypergeometric test for the effect of the partition deacetylation of the sites for the co-regulated (ChIP-chip experience) pairs of genes. For each threshold correlation, the number of pairs of correlations for the genes in the same scheme and are in the same group as the partition is on the threshold has been counted. The number of pairs of correlations for the genes in the same regulation and in the neighboring groups times greater than the threshold value was also counted. The probability of a random drawing of the numbers on these pairs of genes that are on the threshold of the & 39; all pairs of genes that have the same controller is a hypergeometric distribution.
Table 5Le importance of the number of groups responsible for the partition of Histone deacetylation. The statistical significance of the deacetylation of histones partition is determined by the proportion of permutations, the largest groups with a maximum correlation than the limit established that the deacetylation of histones partition.
neighboring genes tend to be co-expressed Although many reports have shown that the genes in the vicinity, tend to have the same profiles & 39; expression d [11-14], the co-expression observed can be caused by the spatial arrangement of sensors to access these genes microarrays [20]. To address this potential surround effect & 39; the investigation of the co-expression, we have 269 Kleinstnetzen data, under different conditions, as the chip drawings according to the data. To assess & 39; l & 39; importance of the co-expression of genes between neighbours, we have the test of the adjacent pairs hypergeometric correlations between genes and between genes. For each threshold correlation, we counted the number of pairs of correlations on the threshold of adjacent genes, and that for all pairs of genes, regardless of their physical location. The number of genes neighboring above & 39; has a threshold hypergeometric distribution & 39; null hypothesis. The results are summarized in Table 1. As the p-values in the table indicate the co-expression of genes neighbors is important for everyone as a threshold value (from 0.5 to 0.9). The deacetylation of the sites reduce the correlations between genes adjacent to check & 39; the assumption that the deacetylation chromatin sites, the correlation between the expression of genes & 39; neighbors, we again an attempt hypergeometric. For each threshold correlation, we counted the number of pairs of correlations on the threshold of all adjacent genes, the genes for all adjacent separated by a deacetylation. The number of genes with deacetylaiton adjacent areas between them over the threshold hypergeometrically is under the zero hypothesis & 39;. The results in Table 2 indicate that the partition is significant effect on the delivery of 0.05 threshold values of 0.5 to 0.9. If a one-sided t test was conducted to explore the relationship between genes adjacent separated by a deacetylation site and people without deacetylation website, the p-value is 0.0467. This result suggests that the correlation between the expression of genes & 39; adjacent significantly reduced by the presence of deacetylation. Furthermore, in Figure 1, we have the track & 39; expression correlations versus natural distance & 39; logarithmic scale for the neighboring genes without deacetylation. The correlation between & 39; expression of the similarities and the newspaper -0140 physical distances with & 39; interval of 95% (-0168, -0111), which in Figure 2 for the correlation of adjacent genes Separated by a deacetylation -0074 website with 95% confidence interval (-0123, -0024). He says that if two genes are neighbors together physically, they are suitable & 39; co-expressed. However, the deacetylation sites can reduce the correlation between the physical and the gap & 39; expression similarity. Tests mounted on the co-regulation and the groups of YPD ChIP-chip experience, as the two factors of transcription and chromatin status is the & 39; expression of genes, we also have an impact on the status of chromatin regulators share of genes. We have 294 groups in the co-regulation YPD (Yeast Proteome Database " in March 2004 [21]) and calculates the couples in & 39; correlations within individual groups. The co-regulation in the genes audiences d & 39; a regulator. The deacetylation of the places created by the genome were used for the partition of genes in different areas. There are 24833 pairs of genes divides d & 39; a common scheme. Among them, 141 children are genes in the same group deacetylation partition, and 46 pairs of genes belong to neighbors deacetylation partition. We have a hypergeometric test for the 141-litre couple versus & 39; all pairs of genes, and the p-values were significantly (Table 3). We also have a hypergeometirc test for the 46-couple group and & 39; all pairs of genes, and the p-values are not significant in comparison to the 141-pair group (Table 3). The results show that the genes for which regulators are co-when they are in the same partition deacetylation groups. We also have a one-sided t test correlations between regulators and the genes shares deacetylation partition and groups, which jointly by the regulatory authorities in the neighbouring country, but deacetylation partition group and the p-value was 3 10 - 4 This suggests that & 39; there is evidence that the correlation between the regulatory authorities and the genes deacetylation partition divides groups are greater than those between the genes regulators release in the neighbouring country, but the groups. D & 39; In other words, in addition to the sharing of common rules, which belong to the same group deacetylation partition can be another factor, on the co-expression of genes. Besides YPD data, we have also ChIP-chip data [22] to define the objectives of the regulation of transcription factors. A p-value threshold of 0005 was used to draw conclusions about the connection to the regulations for each gene. There are 476649 pairs of genes at least a share scheme, which to this threshold, and we have calculated the correlation couples for these couples. Among all the pairs, 1811 partition deacetylation couples the same group, couples and 1019 are included in the group partition neighbors. The comparisons between the various groups are summarized in Table 4. For the genes in the same partition deacetylation group, according to the number of couples with the relatives of each threshold is much higher than on the & 39; all pairs of genes. But for the genes in the vicinity of the partition deacetylation groups, the difference is & 39; not statistically significant. If we have a one-sided t test for the sample correlations & 39; pair of 1811-and 1019-probe pairs, the p-value is 4 10-8. In Figure 3, we compared the empirical cumulative distributions of the two samples. You can see that the distributions of the correlations are different, and there are more couples with higher pair correlations for the group of 1811 pairs in the same partition as the deacetylation of the group, the neighbor partitions. A single two samples of Kolmogorov-Smirnov test was conducted between the two samples, and it is statistically significant evidence that the two distributions are different (p-value & lt; 0.0001). The test of Kolmogorov-Smirnov is a test to know whether the two samples are from the same distribution, without assumptions on the distribution of the data. Study on the areas of gene & 39; more d & 39; genes neighbors, we also all genes in the same group of the partition at the same time. For each partition group, we have calculated the average correlation, the average absolute correlations, and to correlate. To test l & 39; importance of the relationship we have sample groups of genes in the genome of the size of each group at random times 1000000. For each group of & 39; sample, the correlation average, the average absolute correlations, and the maximum correlation was calculated. The p-value can be estimated, based on the simulation of correlations for these groups. The results are based in Figure 4 shows clearly, the statistical significance of the strong correlation of deacetylation of genes, grouped by websites. Since the presence of these groups can by reasons other than the histones d sac tyl sites, such as the geographical proximity between genes, the neighbours, we also have a different kind of simulations for the assessment of the importance of & 39; correlation Maximum l & 39; within each group. We permeation l & 39; order of the groups on the & 39; entire genome 900000 times. Permut e For each sample, the number of groups that have the maximum correlation of more than 0.6, 0.7, 0.8 or 0.9 counted. We have these groups with a maximum correlation d & 39, a threshold that the groups are qualified. We counted the number & 39; samples permeation with groups that have more than on the basis of the deacetylation of histones observed partition. The statistical significance of the partition can be observed that the percentage of samples with permeation groups, which more than on the basis of the deacetylation of histones observed partition. As Table 5 shows, the results are statistically significant to the threshold of 0.6, 0.7 and 0.8. But the results of the correlation, and the average absolute & 39;-correlations were not statistically significant (data not shown). One possible reason is that many & 39; other supervisors can focus on the process of transcription in & 39; within each partition that led to a significant decrease in the results. To test l & 39; existence & 39; enrichment for the partition function deacetylation groups, the following procedure was performed. There are 1113 deacetylation partition groups with more than one gene & 39; whole. For each of these groups deacetylation partition, the yeast GO Slim terms were mapped with the help of genes & 39; SGD Gene Ontology Mapper Slim [23]. The p-value was calculated by the hypergeometrische by the probability-or more genes, which are particularly m GO Slim end, as MN genes from the GO slim term in the entire genome & 39;. S & 39, there were at least a term GO Slim with p-value less than or equal to 0.0001 deacetylation partition in a group that the man & 39, a group called important. There are 386 large groups of the 1113 partition deacetylation groups, while only 4 out of 100 simulations, the more than 386 groups. The simulation was developed by the group is not sufficient to in the paragraph above. If we all p-values of & 39; all simulations, the 5% percent is 3.02 10-4 in 1113 of 493 groups have at least one term GO Slim with p-value less than or equal to 3, 02 10-4. These results show that the deacetylation partition groups with specific genes Slim GO terms.
Outline discussion
Summary Background Method Results Discussion conclusion of the authors of contributions thanks Notes
L & 39; effect of chromatin to the transcription of genes status arrangement is well known, but his methods remain unattachable. In this article we & 39; the assumption that the deacetylation of histones in chromatin of expression through training of the combined analyses of the various types of data, including data from websites Kleinstnetz deacetylation, L & 39; gene, ChIP-chip data, and YPD database. These analyses have shown that a significant impact on the deacetylation of histone & 39; gene expression patterns. Although we presented results with only 1.95 as a threshold for the definition of deacetylation of sites (which was in the reference [24]), the thresholds (for example, 1.8 and 2.1) give similar results. As an example of the effect of & 39; deacetylation sites, we have two genes, YLR329W and YLR328W, which are separated by a deacetylation site in our analysis. YLR329W (REC102) is a protein that in the early stages of recombination m iotique. The beginning of Meiosis genes that because of the deacetylation of histones in the mitotic cell cycle. They are supported by acetylation of histones in the stadium m iotique [25]. The correlation between these two profiles d & 39; expression of genes is 0.1965. The correlation increases from 0.7499 spores education in the time of data [26], resulting from the Meiosis. This example shows that these two genes are votes when there is no & 39; deacetylation each other, while the correlation is reduced by the presence & 39; deacetylation. The co-expression seen in the neighbors genes in the yeast cell cycle data games are always questionable, because the co-expression is possibly due to the spatial arrangement of the probe on microarrays [20]. In our study, we have 269 Kleinstnetzen data, which under different conditions. Because the chip depending on the model database, the spatial effect & 39; significantly minimized by the combination of a variety of games of the data from different sources. More importantly, the results compare the genes in the same partition deacetylation and the partitions, our neighbours to show that the spatial effect & 39; n is not the reason for the differences. C & 39; is because the spatial effect & 39; should have the same impact in the two conditions. This is further supported by the results of the permutation groups in the score. Besides deacetylation and & 39; acetylation of histones, the methylation of DNA & 39; is another factor for the & 39; epigenetics & 39; impact on the gene . Since Saccharomyces cerevisiae & 39; n is not detectable methylation of DNA & 39; this is a good model for studying the relationship between the way in the areas of deacetylation d & 39; gene. Since deacetylation of histones has been measured in a heterogeneous population, the area of partitions & 39; n is perhaps not an accurate representation d & 39, a special condition. In addition d & 39; other changes to the histones, which also influence the gene & 39; can be ignored, and the need for new studies.
Conclusion The fact that the modification of histones, the transcription of genes, it was for many years. With the high-speed gene microarray gene expression data, and the acetylation & 39; Kleinstnetzen of data, we are able & 39, and the impact of & 39; acetylation of histones in & 39; level of the whole genome. In this article we have the results of the previous & 39; effects of co-expression of genes neighbors. In addition, we have the hypothesis that the & 39; deacetylation of histones sites serve partitions for possible that chromatin & 39; areas of the gene through several approaches. We have the hypothesis that the & 39; deacetylation of histones can lead to higher density to reduce the structure of chromatin and l & 39; accessibility of the factors for the transmission of sequences d & 39; reach their goal. The details of the mechanisms have yet to be examined by the biological experiments.
Outline methods
Summary Background Method Results Discussion conclusion of the authors of contributions thanks Notes
Additional material
Additional file 1
histone deacetylation websites and data d & 39; gene To test our hypothesis that the locations deacetylation as a complex and limited the areas of the district & 39; expression of genes, we have correlated with histone d sac tyl sites profiles d & 39; genetic as follows. The deacetylation of histones were deducted by specific acetylation of histones microarrays [24], where chromatin immunoprecipitation and DNA chips, which are combined to determine l & 39; acetylation of histones. L & 39; increase & 39; acetylation of histones locations in the & 39, 39 & missing; deactylases histone deacetylation were the sites of histones putatifs (1 , 95 times the change in the incidence of fracture) in the wild. The data for the histones d ac tylases RPD3, HDA1, HOS1, HOS2, HOS3 and SIR2 were combined to make the regions interg niques. These data are standardized average acetylation fold changes. Interg niques the region as a deacetylation suspected site, where a whole series of data d & 39; histones d ac tylases is no greater than 1.95. Altogether there are 1747 pages putatifs deacetylation. The suspected sites in the genome were used to the group of genes areas. We have 269 Kleinstnetzen yeast database (NCBI GEO downloaded databases [27], there are 6132 with Gene & lt; 25% = missing data in the totality of the experience & 39;) l & amp ;; 39; analysis d & 39; gene. Altogether there are 1574 groups deacetylation. Among them, 461 deacetylation groups contain a single gene, and 315, 183, 149 and 121, the groups of 2, 3, 4 and 5 genes. The entry d & 39; information group in the 1st Additional Protocol The statistical analyses of the correlation coefficients were calculated by Pearson, for the data d & 39; gene. The hypergeometric tests were performed for evaluating the importance & 39, the co-regulation between the effects of neighboring genes, the importance of & 39; partition effect of chromatin deacetylation websites, and the impact of the common status Chromatin transfer the distribution of genes regulators. One-sided t-tests were conducted to explore the genes in the same partition deacetylation of the groups and those of our neighbours partition groups. The partiality two samples Kolmogorov-Smirnov test was made to test whether a difference between the distribution of the correlations for the release of the same genes regulators and deacetylation partition, and that the groups that are the same genes regulating authorities, but groups of neighbors. The authors of the contributions
LC & 39; procedure for the analysis of data and has been involved in the preparation of the manuscript. HZ monitored l & 39; study and helped to create the index. Both authors read and approved the final manuscript.
Acknowledgements This work was partly funded by the NSF grant DMS 0241160.
Outline references
Summary Background Method Results Discussion conclusion of the authors of contributions thanks Notes
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