Understanding variation in transcription factor binding by modeling transcription factor genome-epigenome interactions

Despite explosive growth in genomic datasets, the methods for studying epigenomic mechanisms of gene regulation remain primitive. Here we present a model-based approach to systematically analyze the epigenomic functions in modulating transcription factor-DNA binding. Based on the first principles of statistical mechanics, this model considers the interactions between epigenomic modifications and a cis-regulatory module, which contains multiple binding sites arranged in any configurations. We compiled a comprehensive epigenomic dataset in mouse embryonic stem (mES) cells, including DNA methylation (MeDIP-seq and MRE-seq), DNA hydroxymethylation (5-hmC-seq), and histone modifications (ChIP-seq). We discovered correlations of transcription factors (TFs) for specific combinations of epigenomic modifications, which we term epigenomic motifs. Epigenomic motifs explained why some TFs appeared to have different DNA binding motifs derived from in vivo (ChIP-seq) and in vitro experiments. Theoretical analyses suggested that the epigenome can modulate transcriptional noise and boost the cooperativity of weak TF binding sites. ChIP-seq data suggested that epigenomic boost of binding affinities in weak TF binding sites can function in mES cells. We showed in theory that the epigenome should suppress the TF binding differences on SNP-containing binding sites in two people. Using personal data, we identified strong associations between H3K4me2/H3K9ac and the degree of personal differences in NFκB binding in SNP-containing binding sites, which may explain why some SNPs introduce much smaller personal variations on TF binding than other SNPs. In summary, this model presents a powerful approach to analyze the functions of epigenomic modifications. This model was implemented into an open source program APEG (Affinity Prediction by Epigenome and Genome, http://systemsbio.ucsd.edu/apeg)

Understanding Variation in Transcription Factor Binding by Modeling Transcription Factor Genome-Epigenome Interactions

Despite explosive growth in genomic datasets, the methods for studying epigenomic mechanisms of gene regulation remain primitive. Here we present a model-based approach to systematically analyze the epigenomic functions in modulating transcription factor-DNA binding. Based on the first principles of statistical mechanics, this model considers the interactions between epigenomic modifications and a cis-regulatory module, which contains multiple binding sites arranged in any configurations. We compiled a comprehensive epigenomic dataset in mouse embryonic stem (mES) cells, including DNA methylation (MeDIP-seq and MRE-seq), DNA hydroxymethylation (5-hmC-seq), and histone modifications (ChIP-seq). We discovered correlations of transcription factors (TFs) for specific combinations of epigenomic modifications, which we term epigenomic motifs. Epigenomic motifs explained why some TFs appeared to have different DNA binding motifs derived from in vivo (ChIP-seq) and in vitro experiments. Theoretical analyses suggested that the epigenome can modulate transcriptional noise and boost the cooperativity of weak TF binding sites. ChIP-seq data suggested that epigenomic boost of binding affinities in weak TF binding sites can function in mES cells. We showed in theory that the epigenome should suppress the TF binding differences on SNP-containing binding sites in two people. Using personal data, we identified strong associations between H3K4me2/H3K9ac and the degree of personal differences in NFκB binding in SNP-containing binding sites, which may explain why some SNPs introduce much smaller personal variations on TF binding than other SNPs. In summary, this model presents a powerful approach to analyze the functions of epigenomic modifications. This model was implemented into an open source program APEG (Affinity Prediction by Epigenome and Genome, http://systemsbio.ucsd.edu/apeg).</p

Users Collaborative Mix-Zone to Resist the Query Content and Time Interval Correlation Attacks

In location-based services of continuous query, it is easier than snapshot to confirm whether a location belongs to a particular user, because sole location can be composed into a trajectory by profile correlation. In order to cut off the correlation and disturb the sub-trajectory, an un-detective region called mix-zone was proposed. However, at the time of this writing, the existing algorithms of this type mainly focus on the profiles of ID, passing time, transition probability, mobility patterns as well as road characteristics. In addition, there is still no standard way of coping with attacks of correlating each location by mining out query content and time interval from the sub-trajectory. To cope with such types of attack, users have to generalize their query contents and time intervals similarity. Hence, this paper first provided an attack model to simulate the adversary correlating the real location with a higher probability of query content and time interval similarity. Then a user collaboration mix-zone (CoMix) that can generalize these two types of profiles is proposed, so as to achieve location privacy. In CoMix, each user shares the common profile set to lowering the probability of success opponents to get the actual position through the correlation of location. Thirdly, entropy is utilized to measure the level of privacy preservation. At last, this paper further verifies the effectiveness and efficiency of the proposed algorithm by experimental evaluations

Inhibition of Caspase-3, -6, -8 and -9 Expression in Rats with Acute Spinal Cord Injury by Cantharidin Treatment

Purpose: To demonstrate the anti-apoptotic effects of cantharidin in mice with acute spinal cord injury (ASCI).Methods: In total, 30 male Sprague-Dawley mice were divided into three groups of 10 animals each. ASCI was induced in two of the groups using a modified Allen's method, consisting of treatment with 10 mg/kg body weight cantharidin after injury, and sacrifice on days 2, 5, 10, 20 and 30 to extract the spinal cord. The activity levels of caspase-3, -6, -8, and -9 were determined spectrophotometrically at 455 nm with a microplate reader.Results: The results showed that cantharidin treatment caused a significant reduction in the expression levels of all four caspases – caspase-3, -6, -8, and -9 – compared with the untreated groups. Two hours after ASCI, caspase levels in the cantharidin-treated group increased, reaching maximum after day 5, but were significantly lower than in the untreated group. The expression levels of caspases in the cantharidin-treated group were similar to those in the control group on days 20 and 30 following ASCI (p&gt; 0.05).Conclusion: Cantharidin treatment exerts an anti-apoptotic effect against secondary spinal cord injury (SCI) by suppressing caspase activity. Thus, cantharidin may be suitable for the treatment of secondary SCI.Keywords: Cantharidin, Caspase, Anti-apoptotic, Inhibition, Regeneratio