Nucleosomal Context of Binding Sites Influences Transcription Factor Binding Affinity and Gene Regulation

Transcription factor (TF) binding to its DNA target site plays an essential role in gene regulation. The location, orientation and spacing of transcription factor binding sites (TFBSs) also affect regulatory function of the TF. However, how nucleosomal context of TFBSs influences TF binding and subsequent gene regulation remains to be elucidated. Using genome-wide nucleosome positioning and TF binding data in budding yeast, we found that binding affinities of TFs to DNA tend to decrease with increasing nucleosome occupancy of the associated binding sites. We further demonstrated that nucleosomal context of binding sites is correlated with gene regulation of the corresponding TF. Nucleosome-depleted TFBSs are linked to high gene activity and low expression noise, whereas nucleosome-covered TFBSs are associated with low gene activity and high expression noise. Moreover, nucleosome-covered TFBSs tend to disrupt coexpression of the corresponding TF target genes. We conclude that nucleosomal context of binding sites influences TF binding affinity, subsequently affecting the regulation of TFs on their target genes. This emphasizes the need to include nucleosomal context of TFBSs in modeling gene regulation

Robustness of transcriptional regulatory program influences gene expression variability

<p>Abstract</p> <p>Background</p> <p>Most genes are not affected when any transcription factor (TF) is knocked out, indicating that they have robust transcriptional regulatory program. Yet the mechanism underlying robust transcriptional regulatory program is less clear.</p> <p>Results</p> <p>Here, we studied the cause and effect of robust transcriptional regulatory program. We found that cooperative TFs in the robust transcriptional regulatory program regulate their common target genes in an activity-redundant fashion, and they are able to compensate for each other's loss. As a result, their target genes are insensitive to their single perturbation. We next revealed that the degree of robustness of transcriptional regulatory program influences gene expression variability. Genes with fragile (unrobust) transcriptional regulatory program under normal growth condition could be readily reprogrammed to significantly modulate gene expression upon changing conditions. They also have high evolutionary rates of gene expression. We further showed that the fragile transcriptional regulatory program is a major source of expression variability.</p> <p>Conclusion</p> <p>We showed that activity-redundant TFs guarantee the robustness of transcriptional regulatory programs, and the fragility of transcriptional regulatory program plays a major role in gene expression variability. These findings reveal the mechanisms underlying robust transcription and expression variability.</p

A game theoretic approach to quantum information

In this project, bridging entropy econometrics, game theory and information theory, a game theoretic approach will be investigated to quantum information, during which new mathematical definitions for quantum relative entropy, quantum mutual information, and quantum channel capacity will be given and monotonicity of entangled quantum relative entropy and additivity of quantum channel capacity will be obtained rigorously in mathematics; also quantum state will be explored in Kelly criterion, during which game theoretic interpretations will be given to classical relative entropy, mutual information, and asymptotical information. In specific, after briefly introducing probability inequalities, C*-algebra, including von Neumann algebra, and quantum probability, we will overview quantum entanglement, quantum relative entropy, quantum mutual information, and entangled quantum channel capacity in the direction of R. L. Stratonovich and V. P. Belavkin, and upon the monotonicity property of quantum mutual information of Araki-Umegaki type and Belavkin-Staszewski type, we will prove the additivity property of entangled quantum channel capacities, extending the results of V. P. Belavkin to products of arbitrary quantum channel to quantum relative entropy of both Araki-Umegaki type and Belavkin-Staszewski type. We will obtain a sufficient condition for minimax theorem in an introduction to strategic game, after which, in the exploration of classical/quantum estimate (here we still use the terminology of quantum estimate in the sense of game theory in accordance to classical estimate, but NOT in the sense of quantum physics or quantum probability), we will find the existence of the minimax value of this game and its minimax strategy, and applying biconjugation in convex analysis, we will arrive at one new approach to quantum relative entropy, quantum mutual entropy, and quantum channel capacity, in the sense, independent on Radon-Nikodym derivative, also the monotonicity of quantum relative entropy and the additivity of quantum communication channel capacity will be obtained. Applying Kelly's criterion, we will give a practical game theoretic interpretation, in the model to identify quantum state, to relative entropy, mutual information, and asymptotical information, during which we will find that the decrement in the doubling rate achieved with true knowledge of the distribution F over that achieved with incorrect knowledge G is bounded by relative entropy R(F;G) of F relative to G; the increment [Delta] in the doubling rate resulting from side information Y is less than or equal to the mutual information I(X,Y); a good sequence to identify the true quantum state leads to asymptotically optimal growth rate of utility; and applying the asymptotic behavior of classical relative entropy, the utility of the Bayes' strategy will be bounded below in terms of the optimal utility. The first two main parts are to extend classical entropy econometrics, in the view of strategic game theory, to non-commutative data, for example, quantum data in physical implementation, while the third main part is to intrinsically and practically give a game theoretic interpretation of classical relative entropy, mutual information, and asymptotical information, in the model to identify quantum state, upon which a pregnant financial stock may be designed, which may be called "quantum" stock, for its physical implementation

A game theoretic approach to quantum information

In this project, bridging entropy econometrics, game theory and information theory, a game theoretic approach will be investigated to quantum information, during which new mathematical definitions for quantum relative entropy, quantum mutual information, and quantum channel capacity will be given and monotonicity of entangled quantum relative entropy and additivity of quantum channel capacity will be obtained rigorously in mathematics; also quantum state will be explored in Kelly criterion, during which game theoretic interpretations will be given to classical relative entropy, mutual information, and asymptotical information. In specific, after briefly introducing probability inequalities, C*-algebra, including von Neumann algebra, and quantum probability, we will overview quantum entanglement, quantum relative entropy, quantum mutual information, and entangled quantum channel capacity in the direction of R. L. Stratonovich and V. P. Belavkin, and upon the monotonicity property of quantum mutual information of Araki-Umegaki type and Belavkin-Staszewski type, we will prove the additivity property of entangled quantum channel capacities, extending the results of V. P. Belavkin to products of arbitrary quantum channel to quantum relative entropy of both Araki-Umegaki type and Belavkin-Staszewski type. We will obtain a sufficient condition for minimax theorem in an introduction to strategic game, after which, in the exploration of classical/quantum estimate (here we still use the terminology of quantum estimate in the sense of game theory in accordance to classical estimate, but NOT in the sense of quantum physics or quantum probability), we will find the existence of the minimax value of this game and its minimax strategy, and applying biconjugation in convex analysis, we will arrive at one new approach to quantum relative entropy, quantum mutual entropy, and quantum channel capacity, in the sense, independent on Radon-Nikodym derivative, also the monotonicity of quantum relative entropy and the additivity of quantum communication channel capacity will be obtained. Applying Kelly's criterion, we will give a practical game theoretic interpretation, in the model to identify quantum state, to relative entropy, mutual information, and asymptotical information, during which we will find that the decrement in the doubling rate achieved with true knowledge of the distribution F over that achieved with incorrect knowledge G is bounded by relative entropy R(F;G) of F relative to G; the increment [Delta] in the doubling rate resulting from side information Y is less than or equal to the mutual information I(X,Y); a good sequence to identify the true quantum state leads to asymptotically optimal growth rate of utility; and applying the asymptotic behavior of classical relative entropy, the utility of the Bayes' strategy will be bounded below in terms of the optimal utility. The first two main parts are to extend classical entropy econometrics, in the view of strategic game theory, to non-commutative data, for example, quantum data in physical implementation, while the third main part is to intrinsically and practically give a game theoretic interpretation of classical relative entropy, mutual information, and asymptotical information, in the model to identify quantum state, upon which a pregnant financial stock may be designed, which may be called "quantum" stock, for its physical implementation

Do maternal health problems influence child's worrying status? Evidence from British cohort study

The influence of maternal health problems on child's worrying status is important in practice in terms of the intervention of maternal health problems early for the influence on child's worrying status. Conventional methods apply symmetric prior distributions such as a normal distribution or a Laplace distribituion for regression coefficients, which may be suitable for median regression and exhibit no robustness to outliers. This paper develops a quantile regression on linear panel data model without heterogeneity from a Bayesian point of view, and examines the influence of maternal health problems on child's worrying status. Upon a location-scale mixture representation of the asymmetric Laplace error distribution, this paper provides how the posterior distribution can be sampled and summarized by Markov chain Monte Carlo method. Applying for the 1970 British Cohort Study data, we find and that a different maternal health problem has different influence on child's worrying status at different quantiles. In addition, applying stochastic search variable selection for maternal health problems in the 1970 British Cohort Study data, we find that maternal nervous breakdown, in our work, among the 25 maternal health problems, contributes most to influence the child's worrying status

Insights into distinct regulatory modes of nucleosome positioning

<p>Abstract</p> <p>Background</p> <p>The nucleosome is the fundamental unit of eukaryotic genomes. Experimental evidence suggests that the genomic DNA sequence and a variety of protein factors contribute to nucleosome positioning <it>in vivo</it>. However, how nucleosome positioning is determined locally is still largely unknown.</p> <p>Results</p> <p>We found that transcription factor binding sites (TFBSs) with particular nucleosomal contexts show a preference to reside on specific chromosomes. We identified four typical gene classes associated with distinct regulatory modes of nucleosome positioning, and further showed that they are distinguished by transcriptional regulation patterns. The first mode involves the cooperativity between chromatin remodeling and stable transcription factor (TF)-DNA binding that is linked to high intrinsic DNA binding affinities, evicting nucleosomes from favorable DNA sequences. The second is the DNA-encoded low nucleosome occupancy that is associated with high gene activity. The third is through chromatin remodeling and histone acetylation, sliding nucleosomes along DNA. This mode is linked to more cryptic sites for TF binding. The last consists of the nucleosome-enriched organization driven by other factors that overrides nucleosome sequence preferences. In addition, we showed that high polymerase II (Pol II) occupancy is associated with high nucleosome occupancy around the transcription start site (TSS).</p> <p>Conclusions</p> <p>We identified four different regulatory modes of nucleosome positioning and gave insights into mechanisms that specify promoter nucleosome location. We suggest two distinct modes of recruitment of Pol II, which are selectively employed by different genes.</p

Two distinct modes of nucleosome modulation associated with different degrees of dependence of nucleosome positioning on the underlying DNA sequence

<p>Abstract</p> <p>Background</p> <p>The nucleosome is the fundamental unit of eukaryotic genomes. Its positioning plays a central role in diverse cellular processes that rely on access to genomic DNA. Experimental evidence suggests that the genomic DNA sequence is one important determinant of nucleosome positioning. Yet it is less clear whether the role of the underlying DNA sequence in nucleosome positioning varies across different promoters. Whether different determinants of nucleosome positioning have characteristic influences on nucleosome modulation also remains to be elucidated.</p> <p>Results</p> <p>We identified two typical promoter classes in yeast associated with high or low dependence of nucleosome positioning on the underlying DNA sequence, respectively. Importantly, the two classes have low or high intrinsic sequence preferences for nucleosomes, respectively. The two classes are further distinguished by multiple promoter features, including nucleosome occupancy, nucleosome fuzziness, H2A.Z occupancy, changes in nucleosome positions before and after transcriptional perturbation, and gene activity. Both classes have significantly high turnover rates of histone H3, but employ distinct modes of nucleosome modulation: The first class is characterized by hyperacetylation, whereas the second class is highly regulated by ATP-dependent chromatin remodelling.</p> <p>Conclusion</p> <p>Our results, coupled with the known features of nucleosome modulation, suggest that the two distinct modes of nucleosome modulation selectively employed by different genes are linked with the intrinsic sequence preferences for nucleosomes. The difference in modes of nucleosome modulation can account for the difference in the contribution of DNA sequence to nucleosome positioning between both promoter classes.</p

Genome-wide analysis of the effect of histone modifications on the coexpression of neighboring genes in Saccharomyces cerevisiae

<p>Abstract</p> <p>Background</p> <p>Neighboring gene pairs in the genome of <it>Saccharomyces cerevisiae </it>have a tendency to be expressed at the same time. The distribution of histone modifications along chromatin fibers is suggested to be an important mechanism responsible for such coexpression. However, the extent of the contribution of histone modifications to the coexpression of neighboring genes is unclear.</p> <p>Results</p> <p>We investigated the similarity of histone modification between neighboring genes using autocorrelation analysis and composite profiles. Our analysis showed that neighboring genes had similar levels or changes of histone modifications, especially those transcribed in the same direction. The similarities, however, were restricted to 1 or 2 neighboring genes. Moreover, the expression of a gene was significantly correlated with histone modification of its neighboring gene(s), but this was limited to only 1 or 2 neighbors. Using a hidden Markov model (HMM), we found more than 2000 chromatin domains with similar acetylation changes as the cultures changed and a considerable number of these domains covered 2-4 genes. Gene pairs within domains exhibited a higher level of coexpression than random pairs and shared similar functions.</p> <p>Conclusions</p> <p>The results of this study suggest that similar histone modifications occur within only a small local chromatin region in yeast. The modifications generally have an effect on coexpression with only 1 or 2 neighboring genes. Some blocking mechanism(s) might strictly restrain the distribution of histone modifications in yeast.</p