RESUMO
Boolean networks are largely employed to model the qualitative dynamics of cell fate processes by describing the change of binary activation states of genes and transcription factors with time. Being able to bridge such qualitative states with quantitative measurements of gene expression in cells, as scRNA-seq, is a cornerstone for data-driven model construction and validation. On one hand, scRNA-seq binarisation is a key step for inferring and validating Boolean models. On the other hand, the generation of synthetic scRNA-seq data from baseline Boolean models provides an important asset to benchmark inference methods. However, linking characteristics of scRNA-seq datasets, including dropout events, with Boolean states is a challenging task. We present scBoolSeq, a method for the bidirectional linking of scRNA-seq data and Boolean activation state of genes. Given a reference scRNA-seq dataset, scBoolSeq computes statistical criteria to classify the empirical gene pseudocount distributions as either unimodal, bimodal, or zero-inflated, and fit a probabilistic model of dropouts, with gene-dependent parameters. From these learnt distributions, scBoolSeq can perform both binarisation of scRNA-seq datasets, and generate synthetic scRNA-seq datasets from Boolean traces, as issued from Boolean networks, using biased sampling and dropout simulation. We present a case study demonstrating the application of scBoolSeq's binarisation scheme in data-driven model inference. Furthermore, we compare synthetic scRNA-seq data generated by scBoolSeq with BoolODE's, data for the same Boolean Network model. The comparison shows that our method better reproduces the statistics of real scRNA-seq datasets, such as the mean-variance and mean-dropout relationships while exhibiting clearly defined trajectories in two-dimensional projections of the data.
Assuntos
Biologia Computacional , Análise de Célula Única , Biologia Computacional/métodos , Análise de Célula Única/métodos , Análise de Célula Única/estatística & dados numéricos , Humanos , RNA-Seq/métodos , RNA-Seq/estatística & dados numéricos , Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/estatística & dados numéricos , Análise de Sequência de RNA/métodos , Análise de Sequência de RNA/estatística & dados numéricos , Algoritmos , Redes Reguladoras de Genes/genética , Modelos Estatísticos , Software , Análise da Expressão Gênica de Célula ÚnicaRESUMO
Psoriasis arises from complex interactions between keratinocytes and immune cells, leading to uncontrolled inflammation, immune hyperactivation, and a perturbed keratinocyte life cycle. Despite the availability of drugs for psoriasis management, the disease remains incurable. Treatment response variability calls for new tools and approaches to comprehend the mechanisms underlying disease development. We present a Boolean multiscale population model that captures the dynamics of cell-specific phenotypes in psoriasis, integrating discrete logical formalism and population dynamics simulations. Through simulations and network analysis, the model predictions suggest that targeting neutrophil activation in conjunction with inhibition of either prostaglandin E2 (PGE2) or STAT3 shows promise comparable to interleukin-17 (IL-17) inhibition, one of the most effective treatment options for moderate and severe cases. Our findings underscore the significance of considering complex intercellular interactions and intracellular signaling in psoriasis and highlight the importance of computational approaches in unraveling complex biological systems for drug target identification.
RESUMO
Multiscale models provide a unique tool for studying complex processes that study events occurring at different scales across space and time. In the context of biological systems, such models can simulate mechanisms happening at the intracellular level such as signaling, and at the extracellular level where cells communicate and coordinate with other cells. They aim to understand the impact of genetic or environmental deregulation observed in complex diseases, describe the interplay between a pathological tissue and the immune system, and suggest strategies to revert the diseased phenotypes. The construction of these multiscale models remains a very complex task, including the choice of the components to consider, the level of details of the processes to simulate, or the fitting of the parameters to the data. One additional difficulty is the expert knowledge needed to program these models in languages such as C++ or Python, which may discourage the participation of non-experts. Simplifying this process through structured description formalisms - coupled with a graphical interface - is crucial in making modeling more accessible to the broader scientific community, as well as streamlining the process for advanced users. This article introduces three examples of multiscale models which rely on the framework PhysiBoSS, an add-on of PhysiCell that includes intracellular descriptions as continuous time Boolean models to the agent-based approach. The article demonstrates how to easily construct such models, relying on PhysiCell Studio, the PhysiCell Graphical User Interface. A step-by-step tutorial is provided as a Supplementary Material and all models are provided at: https://physiboss.github.io/tutorial/.
RESUMO
The efficiency of analyzing high-throughput data in systems biology has been demonstrated in numerous studies, where molecular data, such as transcriptomics and proteomics, offers great opportunities for understanding the complexity of biological processes. One important aspect of data analysis in systems biology is the shift from a reductionist approach that focuses on individual components to a more integrative perspective that considers the system as a whole, where the emphasis shifted from differential expression of individual genes to determining the activity of gene sets. Here, we present the rROMA software package for fast and accurate computation of the activity of gene sets with coordinated expression. The rROMA package incorporates significant improvements in the calculation algorithm, along with the implementation of several functions for statistical analysis and visualizing results. These additions greatly expand the package's capabilities and offer valuable tools for data analysis and interpretation. It is an open-source package available on github at: www.github.com/sysbio-curie/rROMA . Based on publicly available transcriptomic datasets, we applied rROMA to cystic fibrosis, highlighting biological mechanisms potentially involved in the establishment and progression of the disease and the associated genes. Results indicate that rROMA can detect disease-related active signaling pathways using transcriptomic and proteomic data. The results notably identified a significant mechanism relevant to cystic fibrosis, raised awareness of a possible bias related to cell culture, and uncovered an intriguing gene that warrants further investigation.