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An information theoretic treatment of sequence-to-expression modeling.

ABSTRACT: Studying a gene's regulatory mechanisms is a tedious process that involves identification of candidate regulators by transcription factor (TF) knockout or over-expression experiments, delineation of enhancers by reporter assays, and demonstration of direct TF influence by site mutagenesis, among other approaches. Such experiments are often chosen based on the biologist's intuition, from several testable hypotheses. We pursue the goal of making this process systematic by using ideas from information theory to reason about experiments in gene regulation, in the hope of ultimately enabling rigorous experiment design strategies. For this, we make use of a state-of-the-art mathematical model of gene expression, which provides a way to formalize our current knowledge of cis- as well as trans- regulatory mechanisms of a gene. Ambiguities in such knowledge can be expressed as uncertainties in the model, which we capture formally by building an ensemble of plausible models that fit the existing data and defining a probability distribution over the ensemble. We then characterize the impact of a new experiment on our understanding of the gene's regulation based on how the ensemble of plausible models and its probability distribution changes when challenged with results from that experiment. This allows us to assess the 'value' of the experiment retroactively as the reduction in entropy of the distribution (information gain) resulting from the experiment's results. We fully formalize this novel approach to reasoning about gene regulation experiments and use it to evaluate a variety of perturbation experiments on two developmental genes of D. melanogaster. We also provide objective and 'biologist-friendly' descriptions of the information gained from each such experiment. The rigorously defined information theoretic approaches presented here can be used in the future to formulate systematic strategies for experiment design pertaining to studies of gene regulatory mechanisms.

SUBMITTER: Khajouei F

PROVIDER: S-EPMC6175532 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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An information theoretic treatment of sequence-to-expression modeling.

Khajouei Farzaneh F Sinha Saurabh S

PLoS computational biology 20180926 9

Studying a gene's regulatory mechanisms is a tedious process that involves identification of candidate regulators by transcription factor (TF) knockout or over-expression experiments, delineation of enhancers by reporter assays, and demonstration of direct TF influence by site mutagenesis, among other approaches. Such experiments are often chosen based on the biologist's intuition, from several testable hypotheses. We pursue the goal of making this process systematic by using ideas from informat ...[more]

PMID: 30256780

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Project description:BACKGROUND:DNA methylation is a stable form of epigenetic memory used by cells to control gene expression. Whole genome bisulfite sequencing (WGBS) has emerged as a gold-standard experimental technique for studying DNA methylation by producing high resolution genome-wide methylation profiles. Statistical modeling and analysis is employed to computationally extract and quantify information from these profiles in an effort to identify regions of the genome that demonstrate crucial or aberrant epigenetic behavior. However, the performance of most currently available methods for methylation analysis is hampered by their inability to directly account for statistical dependencies between neighboring methylation sites, thus ignoring significant information available in WGBS reads. RESULTS:We present a powerful information-theoretic approach for genome-wide modeling and analysis of WGBS data based on the 1D Ising model of statistical physics. This approach takes into account correlations in methylation by utilizing a joint probability model that encapsulates all information available in WGBS methylation reads and produces accurate results even when applied on single WGBS samples with low coverage. Using the Shannon entropy, our approach provides a rigorous quantification of methylation stochasticity in individual WGBS samples genome-wide. Furthermore, it utilizes the Jensen-Shannon distance to evaluate differences in methylation distributions between a test and a reference sample. Differential performance assessment using simulated and real human lung normal/cancer data demonstrate a clear superiority of our approach over DSS, a recently proposed method for WGBS data analysis. Critically, these results demonstrate that marginal methods become statistically invalid when correlations are present in the data. CONCLUSIONS:This contribution demonstrates clear benefits and the necessity of modeling joint probability distributions of methylation using the 1D Ising model of statistical physics and of quantifying methylation stochasticity using concepts from information theory. By employing this methodology, substantial improvement of DNA methylation analysis can be achieved by effectively taking into account the massive amount of statistical information available in WGBS data, which is largely ignored by existing methods.

Project description:Akaike's information theoretic criterion for model discrimination (AIC) is often stated to "overfit", i.e., it selects models with a higher dimension than the dimension of the model that generated the data. However, with experimental pharmacokinetic data it may not be possible to identify the correct model, because of the complexity of the processes governing drug disposition. Instead of trying to find the correct model, a more useful objective might be to minimize the prediction error of drug concentrations in subjects with unknown disposition characteristics. In that case, the AIC might be the selection criterion of choice. We performed Monte Carlo simulations using a model of pharmacokinetic data (a power function of time) with the property that fits with common multi-exponential models can never be perfect - thus resembling the situation with real data. Prespecified models were fitted to simulated data sets, and AIC and AIC c (the criterion with a correction for small sample sizes) values were calculated and averaged. The average predictive performances of the models, quantified using simulated validation sets, were compared to the means of the AICs. The data for fits and validation consisted of 11 concentration measurements each obtained in 5 individuals, with three degrees of interindividual variability in the pharmacokinetic volume of distribution. Mean AIC c corresponded very well, and better than mean AIC, with mean predictive performance. With increasing interindividual variability, there was a trend towards larger optimal models, but with respect to both lowest AIC c and best predictive performance. Furthermore, it was observed that the mean square prediction error itself became less suitable as a validation criterion, and that a predictive performance measure should incorporate interindividual variability. This simulation study showed that, at least in a relatively simple mixed effects modelling context with a set of prespecified models, minimal mean AIC c corresponded to best predictive performance even in the presence of relatively large interindividual variability.

Project description:BackgroundAlthough Escherichia coli is one of the best studied model organisms, a comprehensive understanding of its gene regulation is not yet achieved. There exist many approaches to reconstruct regulatory interaction networks from gene expression experiments. Mutual information based approaches are most useful for large-scale network inference.ResultsWe used a three-step approach in which we combined gene regulatory network inference based on directed information (DTI) and sequence analysis. DTI values were calculated on a set of gene expression profiles from 19 time course experiments extracted from the Many Microbes Microarray Database. Focusing on influences between pairs of genes in which one partner encodes a transcription factor (TF) we derived a network which contains 878 TF - gene interactions of which 166 are known according to RegulonDB. Afterward, we selected a subset of 109 interactions that could be confirmed by the presence of a phylogenetically conserved binding site of the respective regulator. By this second step, the fraction of known interactions increased from 19% to 60%. In the last step, we checked the 44 of the 109 interactions not yet included in RegulonDB for functional relationships between the regulator and the target and, thus, obtained ten TF - target gene interactions. Five of them concern the regulator LexA and have already been reported in the literature. The remaining five influences describe regulations by Fis (with two novel targets), PhdR, PhoP, and KdgR. For the validation of our approach, one of them, the regulation of lipoate synthase (LipA) by the pyruvate-sensing pyruvate dehydrogenate repressor (PdhR), was experimentally checked and confirmed.ConclusionsWe predicted a set of five novel TF - target gene interactions in E. coli. One of them, the regulation of lipA by the transcriptional regulator PdhR was validated experimentally. Furthermore, we developed DTInfer, a new R-package for the inference of gene-regulatory networks from microarrays using directed information.

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An information theoretic treatment of sequence-to-expression modeling.

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An information theoretic treatment of sequence-to-expression modeling.

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