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The advent of high-throughput sequencing has made it possible to measure the expression of genes at relatively low cost. However, direct measurement of regulatory mechanisms, such as transcription factor (TF) activity is still not readily feasible in a high-throughput manner. Consequently, there is a need for computational approaches that can reliably estimate regulator activity from observable gene expression data. In this work, we present a noisy Boolean logic Bayesian model for TF activity inference from differential gene expression data and causal graphs. Our approach provides a flexible framework to incorporate biologically motivated TF-gene regulation logic models. Using simulations and controlled over-expression experiments in cell cultures, we demonstrate that our method can accurately identify TF activity. Moreover, we apply our method to bulk and single cell transcriptomics measurements to investigate transcriptional regulation of fibroblast phenotypic plasticity. Finally, to facilitate usage, we provide user-friendly software packages and a web-interface to query TF activity from user input differential gene expression data: https://umbibio.math.umb.edu/nlbayes/., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Insufficient dietary intake of vitamin A causes various human diseases. For instance, chronic vitamin A deprivation causes blindness, slow growth, impaired immunity, and an increased risk of mortality in children. In contrast to these diverse effects of vitamin A deficiency (VAD) in mammals, chronic VAD in flies neither causes obvious developmental defects nor lethality. As in mammals, VAD in flies severely affects the visual system: it impairs the synthesis of the retinal chromophore, disrupts the formation of the visual pigments (Rhodopsins), and damages the photoreceptors. However, the molecular mechanisms that respond to VAD remain poorly understood. To identify genes and signaling pathways that are affected by VAD, we performed RNA-sequencing and differential gene expression analysis in Drosophila melanogaster. We found an upregulation of genes that are essential for the synthesis of the retinal chromophore, specific aminoacyl-tRNA synthetases, and major nutrient reservoir proteins. We also discovered that VAD affects several genes that are required for the termination of the light response: for instance, we found a downregulation of both arrestin genes that are essential for the inactivation of Rhodopsin. A comparison of the VAD-responsive genes with previously identified blue light stress-responsive genes revealed that the two types of environmental stress trigger largely nonoverlapping transcriptome responses. Yet, both stresses increase the expression of seven genes with poorly understood functions. Taken together, our transcriptome analysis offers insights into the molecular mechanisms that respond to environmental stresses., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

Motivation: Over the past decade, there have been impressive advances in determining the 3D structures of protein complexes. However, there are still many complexes with unknown structures, even when the structures of the individual proteins are known. The advent of protein sequence information provides an opportunity to leverage evolutionary information to enhance the accuracy of protein-protein interface prediction. To this end, several statistical and machine learning methods have been proposed. In particular, direct coupling analysis has recently emerged as a promising approach for identification of protein contact maps from sequential information. However, the ability of these methods to detect protein-protein inter-residue contacts remains relatively limited., Results: In this work, we propose a method to integrate sequential and co-evolution information with structural and functional information to increase the performance of protein-protein interface prediction. Further, we present a post-processing clustering method that improves the average relative F1 score by 70% and 24% and the average relative precision by 80% and 36% in comparison with two state-of-the-art methods, PSICOV and GREMLIN., Availability and Implementation: https://github.com/BioMLBoston/PatchDCA., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Inference of active regulatory mechanisms underlying specific molecular and environmental perturbations is essential for understanding cellular response. The success of inference algorithms relies on the quality and coverage of the underlying network of regulator-gene interactions. Several commercial platforms provide large and manually curated regulatory networks and functionality to perform inference on these networks. Adaptation of such platforms for open-source academic applications has been hindered by the lack of availability of accurate, high-coverage networks of regulatory interactions and integration of efficient causal inference algorithms. In this work, we present CIE, an integrated platform for causal inference of active regulatory mechanisms form differential gene expression data. Using a regularized Gaussian Graphical Model, we construct a transcriptional regulatory network by integrating publicly available ChIP-seq experiments with gene-expression data from tissue-specific RNA-seq experiments. Our GGM approach identifies high confidence transcription factor (TF)-gene interactions and annotates the interactions with information on mode of regulation (activation vs. repression). Benchmarks against manually curated databases of TF-gene interactions show that our method can accurately detect mode of regulation. We demonstrate the ability of our platform to identify active transcriptional regulators by using controlled in vitro overexpression and stem-cell differentiation studies and utilize our method to investigate transcriptional mechanisms of fibroblast phenotypic plasticity., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Motivation: Understanding and predicting an individual's response in a clinical trial is the key to better treatments and cost-: effective medicine. Over the coming years, more and more large-scale omics datasets will become available to characterize patients with complex and heterogeneous diseases at a molecular level. Unfortunately, genetic, phenotypical and environmental variation is much higher in a human trial population than currently modeled or measured in most animal studies. In our experience, this high variability can lead to failure of trained predictors in independent studies and undermines the credibility and utility of promising high-dimensional datasets., Methods: We propose a method that utilizes patient-level genome-wide expression data in conjunction with causal networks based on prior knowledge. Our approach determines a differential expression profile for each patient and uses a Bayesian approach to infer corresponding upstream regulators. These regulators and their corresponding posterior probabilities of activity are used in a regularized regression framework to predict response., Results: We validated our approach using two clinically relevant phenotypes, namely acute rejection in kidney transplantation and response to Infliximab in ulcerative colitis. To demonstrate pitfalls in translating trained predictors across independent trials, we analyze performance characteristics of our approach as well as alternative feature sets in the regression on two independent datasets for each phenotype. We show that the proposed approach is able to successfully incorporate causal prior knowledge to give robust performance estimates., (© The Author 2014. Published by Oxford University Press.)

Motivation: The abundance of many transcripts changes significantly in response to a variety of molecular and environmental perturbations. A key question in this setting is as follows: what intermediate molecular perturbations gave rise to the observed transcriptional changes? Regulatory programs are not exclusively governed by transcriptional changes but also by protein abundance and post-translational modifications making direct causal inference from data difficult. However, biomedical research over the last decades has uncovered a plethora of causal signaling cascades that can be used to identify good candidates explaining a specific set of transcriptional changes., Methods: We take a Bayesian approach to integrate gene expression profiling with a causal graph of molecular interactions constructed from prior biological knowledge. In addition, we define the biological context of a specific interaction by the corresponding Medical Subject Headings terms. The Bayesian network can be queried to suggest upstream regulators that can be causally linked to the altered expression profile., Results: Our approach will treat candidate regulators in the right biological context preferentially, enables hierarchical exploration of resulting hypotheses and takes the complete network of causal relationships into account to arrive at the best set of upstream regulators. We demonstrate the power of our method on distinct biological datasets, namely response to dexamethasone treatment, stem cell differentiation and a neuropathic pain model. In all cases relevant biological insights could be validated., Availability and Implementation: Source code for the method is available upon request.