SERGIO: A Single-Cell Expression Simulator Guided by Gene Regulatory Networks.
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ABSTRACT:
SUBMITTER: Dibaeinia P
PROVIDER: S-EPMC7530147 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundExpression-based phenotype classification using either microarray or RNA-Seq measurements suffers from a lack of specificity because pathway timing is not revealed and expressions are averaged across groups of cells. This paper studies expression-based classification under the assumption that single-cell measurements are sampled at a sufficient rate to detect regulatory timing. Thus, observations are expression trajectories. In effect, classification is performed on data generated by an underlying gene regulatory network.ResultsNetwork regulation is modeled via a Boolean network with perturbation, regulation not fully determined owing to inherent biological randomness. The binary assumption is not critical because the resulting Markov chain characterizes expression trajectories. We assume a partially known Gaussian observation model belonging to an uncertainty class of models. We derive the intrinsically Bayesian robust classifier to discriminate between wild-type and mutated networks based on expression trajectories. The classifier minimizes the expected error across the uncertainty class relative to the prior distribution. We test it using a mammalian cell-cycle model, discriminating between the normal network and one in which gene p27 is mutated, thereby producing a cancerous phenotype. Tests examine all model aspects, including trajectory length, perturbation probability, and the hyperparameters governing the prior distribution over the uncertainty class.ConclusionsSimulations show the rates at which the expected error is diminished by smaller perturbation probability, longer trajectories, and hyperparameters that tighten the prior distribution relative to the unknown true network. For average-expression measurement, methods have been proposed to obtain prior distributions. These should be extended to the more mathematically difficult, but more informative, expression trajectories.
| S-EPMC5872504 | biostudies-literature
Project description:MotivationSingle cell transcriptional profiling opens up a new avenue in studying the functional role of cell-to-cell variability in physiological processes. The analysis of single cell expression profiles creates new challenges due to the distributive nature of the data and the stochastic dynamics of gene transcription process. The reconstruction of gene regulatory networks (GRNs) using single cell transcriptional profiles is particularly challenging, especially when directed gene-gene relationships are desired.ResultsWe developed SINCERITIES (SINgle CEll Regularized Inference using TIme-stamped Expression profileS) for the inference of GRNs from single cell transcriptional profiles. We focused on time-stamped cross-sectional expression data, commonly generated from transcriptional profiling of single cells collected at multiple time points after cell stimulation. SINCERITIES recovers directed regulatory relationships among genes by employing regularized linear regression (ridge regression), using temporal changes in the distributions of gene expressions. Meanwhile, the modes of the gene regulations (activation and repression) come from partial correlation analyses between pairs of genes. We demonstrated the efficacy of SINCERITIES in inferring GRNs using in silico time-stamped single cell expression data and single cell transcriptional profiles of THP-1 monocytic human leukemia cells. The case studies showed that SINCERITIES could provide accurate GRN predictions, significantly better than other GRN inference algorithms such as TSNI, GENIE3 and JUMP3. Moreover, SINCERITIES has a low computational complexity and is amenable to problems of extremely large dimensionality. Finally, an application of SINCERITIES to single cell expression data of T2EC chicken erythrocytes pointed to BATF as a candidate novel regulator of erythroid development.Availability and implementationMATLAB and R version of SINCERITIES are freely available from the following websites: http://www.cabsel.ethz.ch/tools/sincerities.html and https://github.com/CABSEL/SINCERITIES. The single cell THP-1 and T2EC transcriptional profiles are available from the original publications (Kouno et al., 2013; Richard et al., 2016). The in silico single cell data are available on SINCERITIES websites.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC5860204 | biostudies-literature
Project description:Here, we present Scribe (https://github.com/aristoteleo/Scribe-py), a toolkit for detecting and visualizing causal regulatory interactions between genes and explore the potential for single-cell experiments to power network reconstruction. Scribe employs restricted directed information to determine causality by estimating the strength of information transferred from a potential regulator to its downstream target. We apply Scribe and other leading approaches for causal network reconstruction to several types of single-cell measurements and show that there is a dramatic drop in performance for "pseudotime"-ordered single-cell data compared with true time-series data. We demonstrate that performing causal inference requires temporal coupling between measurements. We show that methods such as "RNA velocity" restore some degree of coupling through an analysis of chromaffin cell fate commitment. These analyses highlight a shortcoming in experimental and computational methods for analyzing gene regulation at single-cell resolution and suggest ways of overcoming it.
| S-EPMC7223477 | biostudies-literature
Project description:Single-cell techniques are advancing rapidly and are yielding unprecedented insight into cellular heterogeneity. Mapping the gene regulatory networks (GRNs) underlying cell states provides attractive opportunities to mechanistically understand this heterogeneity. In this review, we discuss recently emerging methods to map GRNs from single-cell transcriptomics data, tackling the challenge of increased noise levels and data sparsity compared with bulk data, alongside increasing data volumes. Next, we discuss how new techniques for single-cell epigenomics, such as single-cell ATAC-seq and single-cell DNA methylation profiling, can be used to decipher gene regulatory programmes. We finally look forward to the application of single-cell multi-omics and perturbation techniques that will likely play important roles for GRN inference in the future.
| S-EPMC6063279 | biostudies-literature
Project description:BackgroundA fundamental fact in biology states that genes do not operate in isolation, and yet, methods that infer regulatory networks for single cell gene expression data have been slow to emerge. With single cell sequencing methods now becoming accessible, general network inference algorithms that were initially developed for data collected from bulk samples may not be suitable for single cells. Meanwhile, although methods that are specific for single cell data are now emerging, whether they have improved performance over general methods is unknown. In this study, we evaluate the applicability of five general methods and three single cell methods for inferring gene regulatory networks from both experimental single cell gene expression data and in silico simulated data.ResultsStandard evaluation metrics using ROC curves and Precision-Recall curves against reference sets sourced from the literature demonstrated that most of the methods performed poorly when they were applied to either experimental single cell data, or simulated single cell data, which demonstrates their lack of performance for this task. Using default settings, network methods were applied to the same datasets. Comparisons of the learned networks highlighted the uniqueness of some predicted edges for each method. The fact that different methods infer networks that vary substantially reflects the underlying mathematical rationale and assumptions that distinguish network methods from each other.ConclusionsThis study provides a comprehensive evaluation of network modeling algorithms applied to experimental single cell gene expression data and in silico simulated datasets where the network structure is known. Comparisons demonstrate that most of these assessed network methods are not able to predict network structures from single cell expression data accurately, even if they are specifically developed for single cell methods. Also, single cell methods, which usually depend on more elaborative algorithms, in general have less similarity to each other in the sets of edges detected. The results from this study emphasize the importance for developing more accurate optimized network modeling methods that are compatible for single cell data. Newly-developed single cell methods may uniquely capture particular features of potential gene-gene relationships, and caution should be taken when we interpret these results.
| S-EPMC6006753 | biostudies-literature
Project description:The inference of gene regulatory networks (GRNs) is crucial to understanding the regulatory mechanisms that govern biological processes. GRNs may be represented as edges in a graph, and hence have been inferred computationally for scRNA-seq data. A wisdom of crowds approach to integrate edges from several GRNs to create one composite GRN has demonstrated improved performance when compared to individual algorithm implementations on bulk RNA-seq and microarray data. In an effort to extend this approach to scRNA-seq data, we present COFFEE (COnsensus single cell-type speciFic inFerence for gEnE regulatory networks), a Borda voting based consensus algorithm that integrates information from 10 established GRN inference methods. We conclude that COFFEE has improved performance across synthetic, curated and experimental datasets when compared to baseline methods. Additionally, we show that a modified version of COFFEE can be leveraged to improve performance on newer cell-type specific GRN inference methods. Overall, our results demonstrate that consensus based methods with pertinent modifications continue to be valuable for GRN inference at the single cell level.
| S-EPMC10802453 | biostudies-literature
Project description:In this paper, we introduce Gene Knockout Inference (GenKI), a virtual knockout (KO) tool for gene function prediction using single-cell RNA sequencing (scRNA-seq) data in the absence of KO samples when only wild-type (WT) samples are available. Without using any information from real KO samples, GenKI is designed to capture shifting patterns in gene regulation caused by the KO perturbation in an unsupervised manner and provide a robust and scalable framework for gene function studies. To achieve this goal, GenKI adapts a variational graph autoencoder (VGAE) model to learn latent representations of genes and interactions between genes from the input WT scRNA-seq data and a derived single-cell gene regulatory network (scGRN). The virtual KO data is then generated by computationally removing all edges of the KO gene-the gene to be knocked out for functional study-from the scGRN. The differences between WT and virtual KO data are discerned by using their corresponding latent parameters derived from the trained VGAE model. Our simulations show that GenKI accurately approximates the perturbation profiles upon gene KO and outperforms the state-of-the-art under a series of evaluation conditions. Using publicly available scRNA-seq data sets, we demonstrate that GenKI recapitulates discoveries of real-animal KO experiments and accurately predicts cell type-specific functions of KO genes. Thus, GenKI provides an in-silico alternative to KO experiments that may partially replace the need for genetically modified animals or other genetically perturbed systems.
| S-EPMC10359630 | biostudies-literature
Project description:Gene regulatory networks (GRNs) drive organism structure and functions, so the discovery and characterization of GRNs is a major goal in biological research. However, accurate identification of causal regulatory connections and inference of GRNs using gene expression datasets, more recently from single-cell RNA-seq (scRNA-seq), has been challenging. Here we employ the innovative method of Causal Inference Using Composition of Transactions (CICT) to uncover GRNs from scRNA-seq data. The basis of CICT is that if all gene expressions were random, a non-random regulatory gene should induce its targets at levels different from the background random process, resulting in distinct patterns in the whole relevance network of gene-gene associations. CICT proposes novel network features derived from a relevance network, which enable any machine learning algorithm to predict causal regulatory edges and infer GRNs. We evaluated CICT using simulated and experimental scRNA-seq data in a well-established benchmarking pipeline and showed that CICT outperformed existing network inference methods representing diverse approaches with many-fold higher accuracy. Furthermore, we demonstrated that GRN inference with CICT was robust to different levels of sparsity in scRNA-seq data, the characteristics of data and ground truth, the choice of association measure and the complexity of the supervised machine learning algorithm. Our results suggest aiming at directly predicting causality to recover regulatory relationships in complex biological networks substantially improves accuracy in GRN inference.
| S-EPMC10612495 | biostudies-literature
Project description:BackgroundExperimental studies of gene expression have identified some of the individual molecular components and elementary reactions that comprise and control cellular behavior. Given our current understanding of gene expression, and the goals of biotechnology research, both scientists and engineers would benefit from detailed simulators that can explicitly compute genome-wide expression levels as a function of individual molecular events, including the activities and interactions of molecules on DNA at single base pair resolution. However, for practical reasons including computational tractability, available simulators have not been able to represent genome-scale models of gene expression at this level of detail.ResultsHere we develop a simulator, TABASCO http://openwetware.org/wiki/TABASCO, which enables the precise representation of individual molecules and events in gene expression for genome-scale systems. We use a single molecule computational engine to track individual molecules interacting with and along nucleic acid polymers at single base resolution. Tabasco uses logical rules to automatically update and delimit the set of species and reactions that comprise a system during simulation, thereby avoiding the need for a priori specification of all possible combinations of molecules and reaction events. We confirm that single molecule, base-pair resolved simulation using TABASCO (Tabasco) can accurately compute gene expression dynamics and, moving beyond previous simulators, provide for the direct representation of intermolecular events such as polymerase collisions and promoter occlusion. We demonstrate the computational capacity of Tabasco by simulating the entirety of gene expression during bacteriophage T7 infection; for reference, the 39,937 base pair T7 genome encodes 56 genes that are transcribed by two types of RNA polymerases active across 22 promoters.ConclusionTabasco enables genome-scale simulation of transcription and translation at individual molecule and single base-pair resolution. By directly representing the position and activity of individual molecules on DNA, Tabasco can directly test the effects of detailed molecular processes on system-wide gene expression. Tabasco would also be useful for studying the complex regulatory mechanisms controlling eukaryotic gene expression. The computational engine underlying Tabasco could also be adapted to represent other types of processive systems in which individual reaction events are organized across a single spatial dimension (e.g., polysaccharide synthesis).
| S-EPMC2242808 | biostudies-literature
Project description:A pressing challenge in single-cell transcriptomics is to benchmark experimental protocols and computational methods. A solution is to use computational simulators, but existing simulators cannot simultaneously achieve three goals: preserving genes, capturing gene correlations, and generating any number of cells with varying sequencing depths. To fill this gap, we propose scDesign2, a transparent simulator that achieves all three goals and generates high-fidelity synthetic data for multiple single-cell gene expression count-based technologies. In particular, scDesign2 is advantageous in its transparent use of probabilistic models and its ability to capture gene correlations via copulas.
| S-EPMC8147071 | biostudies-literature