A Poisson mixture model to identify changes in RNA polymerase II binding quantity using high-throughput sequencing technology

We present a mixture model-based analysis for identifying differences in the distribution of RNA polymerase II (Pol II) in transcribed regions, measured using ChIP-seq (chromatin immunoprecipitation following massively parallel sequencing technology). The statistical model assumes that the number of Pol II-targeted sequences contained within each genomic region follows a Poisson distribution. A Poisson mixture model was then developed to distinguish Pol II binding changes in transcribed region using an empirical approach and an expectation-maximization (EM) algorithm developed for estimation and inference. In order to achieve a global maximum in the M-step, a particle swarm optimization (PSO) was implemented. We applied this model to Pol II binding data generated from hormone-dependent MCF7 breast cancer cells and antiestrogen-resistant MCF7 breast cancer cells before and after treatment with 17β-estradiol (E2). We determined that in the hormone-dependent cells, ~9.9% (2527) genes showed significant changes in Pol II binding after E2 treatment. However, only ~0.7% (172) genes displayed significant Pol II binding changes in E2-treated antiestrogen-resistant cells. These results show that a Poisson mixture model can be used to analyze ChIP-seq data

Towards a Probabilistic Complexity-theoretic Modeling of Biological Cyanide Poisoning as Service Attack in Self-organizing Networks

We draw an analogy of \emph{biological cyanide poisoning} to security attacks in self-organizing mobile ad hoc networks. When a circulatory system is treated as an enclosed network space, a hemoglobin is treated as a mobile node, and a hemoglobin binding with cyanide ion is treated as a compromised node (which cannot bind with oxygen to furnish its oxygen-transport function), we show how cyanide poisoning can reduce the probability of oxygen/message delivery to a rigorously defined ``negligible\u27\u27 quantity. Like formal cryptography, security problem in our network-centric model is defined on the complexity-theoretic concept of ``negligible\u27\u27, which is asymptotically sub-polynomial with respect to a pre-defined system parameter $x$. Intuitively, the parameter $x$ is the key length $n$ in formal cryptography, but is changed to the network scale, or the number of network nodes $N$, in our model. We use the \RP ($n$-runs) complexity class with a virtual oracle to formally model the cyanide poisoning phenomenon and similar network threats. This new analytic approach leads to a new view of biological threats from the perspective of network security and complexity theoretic study

Genome-wide analysis of alternative promoters of human genes using a custom promoter tiling array

<p>Abstract</p> <p>Background</p> <p>Independent lines of evidence suggested that a large fraction of human genes possess multiple promoters driving gene expression from distinct transcription start sites. Understanding which promoter is employed in which cellular context is required to unravel gene regulatory networks within the cell.</p> <p>Results</p> <p>We have developed a custom microarray platform that tiles roughly 35,000 alternative putative promoters from nearly 7,000 genes in the human genome. To demonstrate the utility of this array platform, we have analyzed the patterns of promoter usage in 17β-estradiol (E2)-treated and untreated MCF7 cells and show widespread usage of alternative promoters. Most intriguingly, we show that the downstream promoter in E2-sensitive multiple promoter genes tends to be very close to the 3'-terminus of the gene, suggesting exotic mechanisms of expression regulation in these genes.</p> <p>Conclusion</p> <p>The usage of alternative promoters greatly multiplies the transcriptional complexity available within the human genome. The fact that many of these promoters are incapable of driving the synthesis of a meaningful protein-encoding transcript further complicates the story.</p

Mechanisms of Stress Tolerance in Xerophyte \u3cem\u3eZygophyllum xanthoxylum\u3c/em\u3e and Their Application in Genetic Improvement of Legume Forages

Xerophytes, naturally growing in desert areas, have evolved multiple protective mechanisms to survive and grow well in harsh environments. Zygophyllum xanthoxylum, a succulent xerophyte with excellent adaptability to adverse arid environments and a fodder shrub with high palatability and nutrient value, colonizes arid areas in China and Mongolia. In this study, we found that Z. xanthoxylum grew better responding to salt condition with a typical feature for halophytes and became more tolerant to drought in the presence of moderate salinity (50 mM NaCl); 50 mM NaCl alleviated deleterious impacts of drought on the growth of Z. xanthoxylum by improving the relative water content, inducing a significant drop in leaf water potential and, concomitantly, increasing leaf turgor pressure and chlorophyll concentrations resulting in an enhancement of overall plant photosynthetic activity. Subsequently, co-expression of genes encoding the tonoplast Na+/H+ antiporter (ZxNHX) and H+-PPase (ZxVP1-1) which involve in leaf Na+ accumulation under stress condition by compartmentalizing Na+ into vacuoles in Z. xanthoxylum significantly improved both drought and salt tolerance in legume forages, Lotus corniculatus L. and Medicago sativa L

Diverse histone modifications on histone 3 lysine 9 and their relation to DNA methylation in specifying gene silencing

<p>Abstract</p> <p>Background</p> <p>Previous studies of individual genes have shown that in a self-enforcing way, dimethylation at histone 3 lysine 9 (dimethyl-H3K9) and DNA methylation cooperate to maintain a repressive mode of inactive genes. Less clear is whether this cooperation is generalized in mammalian genomes, such as mouse genome. Here we use epigenomic tools to simultaneously interrogate chromatin modifications and DNA methylation in a mouse leukemia cell line, L1210.</p> <p>Results</p> <p>Histone modifications on H3K9 and DNA methylation in L1210 were profiled by both global CpG island array and custom mouse promoter array analysis. We used chromatin immunoprecipitation microarray (ChIP-chip) to examine acetyl-H3K9 and dimethyl-H3K9. We found that the relative level of acetyl-H3K9 at different chromatin positions has a wider range of distribution than that of dimethyl-H3K9. We then used differential methylation hybridization (DMH) and the restriction landmark genome scanning (RLGS) to analyze the DNA methylation status of the same targets investigated by ChIP-chip. The results of epigenomic profiling, which have been independently confirmed for individual loci, show an inverse relationship between DNA methylation and histone acetylation in regulating gene silencing. In contrast to the previous notion, dimethyl-H3K9 seems to be less distinct in specifying silencing for the genes tested.</p> <p>Conclusion</p> <p>This study demonstrates in L1210 leukemia cells a diverse relationship between histone modifications and DNA methylation in the maintenance of gene silencing. Acetyl-H3K9 shows an inverse relationship between DNA methylation and histone acetylation in regulating gene silencing as expected. However, dimethyl-H3K9 seems to be less distinct in relation to promoter methylation. Meanwhile, a combination of epigenomic tools is of help in understanding the heterogeneity of epigenetic regulation, which may further our vision accumulated from single-gene studies.</p

Inference of hierarchical regulatory network of estrogen-dependent breast cancer through ChIP-based data

<p>Abstract</p> <p>Background</p> <p>Global profiling of in vivo protein-DNA interactions using ChIP-based technologies has evolved rapidly in recent years. Although many genome-wide studies have identified thousands of ERα binding sites and have revealed the associated transcription factor (TF) partners, such as AP1, FOXA1 and CEBP, little is known about ERα associated hierarchical transcriptional regulatory networks.</p> <p>Results</p> <p>In this study, we applied computational approaches to analyze three public available ChIP-based datasets: ChIP-seq, ChIP-PET and ChIP-chip, and to investigate the hierarchical regulatory network for ERα and ERα partner TFs regulation in estrogen-dependent breast cancer MCF7 cells. 16 common TFs and two common new TF partners (RORA and PITX2) were found among ChIP-seq, ChIP-chip and ChIP-PET datasets. The regulatory networks were constructed by scanning the ChIP-peak region with TF specific position weight matrix (PWM). A permutation test was performed to test the reliability of each connection of the network. We then used DREM software to perform gene ontology function analysis on the common genes. We found that FOS, PITX2, RORA and FOXA1 were involved in the up-regulated genes.</p> <p>We also conducted the ERα and Pol-II ChIP-seq experiments in tamoxifen resistance MCF7 cells (denoted as MCF7-T in this study) and compared the difference between MCF7 and MCF7-T cells. The result showed very little overlap between these two cells in terms of targeted genes (21.2% of common genes) and targeted TFs (25% of common TFs). The significant dissimilarity may indicate totally different transcriptional regulatory mechanisms between these two cancer cells.</p> <p>Conclusions</p> <p>Our study uncovers new estrogen-mediated regulatory networks by mining three ChIP-based data in MCF7 cells and ChIP-seq data in MCF7-T cells. We compared the different ChIP-based technologies as well as different breast cancer cells. Our computational analytical approach may guide biologists to further study the underlying mechanisms in breast cancer cells or other human diseases.</p