Inferring gene regulatory networks via transcriptional profiles as associated dynamical attractors
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PROVIDER: PRJNA899050 | ENA |
REPOSITORIES: ENA
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Project description:Inferring gene regulatory networks via transcriptional profiles as associated dynamical attractors
| PRJNA898775 | ENA
Project description:Genetic regulatory networks (GRNs) regulate the flow of genetic information from the genome to expressed messenger RNAs (mRNAs) and thus are critical to controlling the phenotypic characteristics of cells. Numerous methods exist for profiling mRNA transcript levels and identifying protein-DNA binding interactions at the genome-wide scale. These enable researchers to determine the structure and output of transcriptional regulatory networks, but uncovering the complete structure and regulatory logic of GRNs remains a challenge. The field of GRN inference aims to meet this challenge using computational modeling to derive the structure and logic of GRNs from experimental data and to encode this knowledge in Boolean networks, Bayesian networks, ordinary differential equation (ODE) models, or other modeling frameworks. However, most existing models do not incorporate dynamic transcriptional data since it has historically been less widely available in comparison to “static” transcriptional data. We report the development of an evolutionary algorithm-based ODE modeling approach that integrates kinetic transcription data and the theory of attractor dynamics analysis to infer GRN architecture and regulatory logic. Our method outperformed six leading GRN inference methods, all of which do not incorporate kinetic transcriptional data in predicting regulatory connections among TFs when applied to a small-scale engineered synthetic GRN in S. cerevisiae. Moreover, we have shown the potential of our method to predict unknown transcription profiles that would be produced upon genetic perturbation of the GRN governing a two-state phenotypic switch in C. albicans. We established an iterative refinement strategy to facilitate candidate selection for experimentation and the experimental results in turn provide validation or improvement for the model. In this way, our GRN inference approach can expedite the development of a sophisticated mathematical model that accurately describes the structure and dynamics of the in vivo GRN.
2023-06-23 | GSE217461 | GEO
Project description:Genetic regulatory networks (GRNs) regulate the flow of genetic information from the genome to expressed messenger RNAs (mRNAs) and thus are critical to controlling the phenotypic characteristics of cells. Numerous methods exist for profiling mRNA transcript levels and identifying protein-DNA binding interactions at the genome-wide scale. These enable researchers to determine the structure and output of transcriptional regulatory networks, but uncovering the complete structure and regulatory logic of GRNs remains a challenge. The field of GRN inference aims to meet this challenge using computational modeling to derive the structure and logic of GRNs from experimental data and to encode this knowledge in Boolean networks, Bayesian networks, ordinary differential equation (ODE) models, or other modeling frameworks. However, most existing models do not incorporate dynamic transcriptional data since it has historically been less widely available in comparison to “static” transcriptional data. We report the development of an evolutionary algorithm-based ODE modeling approach that integrates kinetic transcription data and the theory of attractor dynamics analysis to infer GRN architecture and regulatory logic. Our method outperformed six leading GRN inference methods, all of which do not incorporate kinetic transcriptional data in predicting regulatory connections among TFs when applied to a small-scale engineered synthetic GRN in S. cerevisiae. Moreover, we have shown the potential of our method to predict unknown transcription profiles that would be produced upon genetic perturbation of the GRN governing a two-state phenotypic switch in C. albicans. We established an iterative refinement strategy to facilitate candidate selection for experimentation and the experimental results in turn provide validation or improvement for the model. In this way, our GRN inference approach can expedite the development of a sophisticated mathematical model that accurately describes the structure and dynamics of the in vivo GRN.
2023-06-23 | GSE217383 | GEO
Project description:Genetic regulatory networks (GRNs) regulate the flow of genetic information from the genome to expressed messenger RNAs (mRNAs) and thus are critical to controlling the phenotypic characteristics of cells. Numerous methods exist for profiling mRNA transcript levels and identifying protein-DNA binding interactions at the genome-wide scale. These enable researchers to determine the structure and output of transcriptional regulatory networks, but uncovering the complete structure and regulatory logic of GRNs remains a challenge. The field of GRN inference aims to meet this challenge using computational modeling to derive the structure and logic of GRNs from experimental data and to encode this knowledge in Boolean networks, Bayesian networks, ordinary differential equation (ODE) models, or other modeling frameworks. However, most existing models do not incorporate dynamic transcriptional data since it has historically been less widely available in comparison to "static" transcriptional data. We report the development of an evolutionary algorithm-based ODE modeling approach (named EA) that integrates kinetic transcription data and the theory of attractor matching to infer GRN architecture and regulatory logic. Our method outperformed six leading GRN inference methods, none of which incorporate kinetic transcriptional data, in predicting regulatory connections among TFs when applied to a small-scale engineered synthetic GRN in Saccharomyces cerevisiae. Moreover, we demonstrate the potential of our method to predict unknown transcriptional profiles that would be produced upon genetic perturbation of the GRN governing a two-state cellular phenotypic switch in Candida albicans. We established an iterative refinement strategy to facilitate candidate selection for experimentation; the experimental results in turn provide validation or improvement for the model. In this way, our GRN inference approach can expedite the development of a sophisticated mathematical model that can accurately describe the structure and dynamics of the in vivo GRN.
| S-EPMC10473541 | 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:Reconstructing transcriptional regulatory networks is an important task in functional genomics. Data obtained from experiments that perturb genes by knockouts or RNA interference contain useful information for addressing this reconstruction problem. However, such data can be limited in size and/or are expensive to acquire. On the other hand, observational data of the organism in steady state (e.g., wild-type) are more readily available, but their informational content is inadequate for the task at hand. We develop a computational approach to appropriately utilize both data sources for estimating a regulatory network. The proposed approach is based on a three-step algorithm to estimate the underlying directed but cyclic network, that uses as input both perturbation screens and steady state gene expression data. In the first step, the algorithm determines causal orderings of the genes that are consistent with the perturbation data, by combining an exhaustive search method with a fast heuristic that in turn couples a Monte Carlo technique with a fast search algorithm. In the second step, for each obtained causal ordering, a regulatory network is estimated using a penalized likelihood based method, while in the third step a consensus network is constructed from the highest scored ones. Extensive computational experiments show that the algorithm performs well in reconstructing the underlying network and clearly outperforms competing approaches that rely only on a single data source. Further, it is established that the algorithm produces a consistent estimate of the regulatory network.
| S-EPMC3938831 | biostudies-literature
Project description:Developmental cell fate decisions are dynamic processes driven by the complex behaviour of gene regulatory networks. A challenge in studying these processes using single-cell genomics is that the data provides only a static snapshot with no detail of dynamics. Metabolic labelling and splicing can provide time-resolved information, but current methods have limitations. Here, we present experimental and computational methods that overcome these limitations to allow dynamical modelling of gene expression from single-cell data. We developed sci-FATE2, an optimised metabolic labelling method that substantially increases data quality, and profiled approximately 45,000 embryonic stem cells differentiating into multiple neural tube identities. To recover dynamics, we developed velvet, a deep learning framework that extends beyond instantaneous velocity estimation by modelling gene expression dynamics through a neural stochastic differential equation system within a variational autoencoder. Velvet outperforms current velocity tools across quantitative benchmarks, and predicts trajectory distributions that accurately recapitulate underlying dataset distributions while conserving known biology. Velvet trajectory distributions capture dynamical aspects such as decision boundaries between alternative fates and correlative gene regulatory structure. Using velvet to provide a dynamical description of in vitro neural patterning, we highlight a process of sequential decision making and fate-specific patterns of developmental signalling. Together, these experimental and computational methods recast single-cell analyses from descriptions of observed data distributions to models of the dynamics that generated them, providing a new framework for investigating developmental gene regulation and cell fate decisions.
2023-07-06 | GSE236378 | GEO
Project description:Developmental cell fate decisions are dynamic processes driven by the complex behaviour of gene regulatory networks. A challenge in studying these processes using single-cell genomics is that the data provides only a static snapshot with no detail of dynamics. Metabolic labelling and splicing can provide time-resolved information, but current methods have limitations. Here, we present experimental and computational methods that overcome these limitations to allow dynamical modelling of gene expression from single-cell data. We developed sci-FATE2, an optimised metabolic labelling method that substantially increases data quality, and profiled approximately 45,000 embryonic stem cells differentiating into multiple neural tube identities. To recover dynamics, we developed velvet, a deep learning framework that extends beyond instantaneous velocity estimation by modelling gene expression dynamics through a neural stochastic differential equation system within a variational autoencoder. Velvet outperforms current velocity tools across quantitative benchmarks, and predicts trajectory distributions that accurately recapitulate underlying dataset distributions while conserving known biology. Velvet trajectory distributions capture dynamical aspects such as decision boundaries between alternative fates and correlative gene regulatory structure. Using velvet to provide a dynamical description of in vitro neural patterning, we highlight a process of sequential decision making and fate-specific patterns of developmental signalling. Together, these experimental and computational methods recast single-cell analyses from descriptions of observed data distributions to models of the dynamics that generated them, providing a new framework for investigating developmental gene regulation and cell fate decisions.
2023-07-06 | GSE236518 | GEO
Project description:Developmental cell fate decisions are dynamic processes driven by the complex behaviour of gene regulatory networks. A challenge in studying these processes using single-cell genomics is that the data provides only a static snapshot with no detail of dynamics. Metabolic labelling and splicing can provide time-resolved information, but current methods have limitations. Here, we present experimental and computational methods that overcome these limitations to allow dynamical modelling of gene expression from single-cell data. We developed sci-FATE2, an optimised metabolic labelling method that substantially increases data quality, and profiled approximately 45,000 embryonic stem cells differentiating into multiple neural tube identities. To recover dynamics, we developed velvet, a deep learning framework that extends beyond instantaneous velocity estimation by modelling gene expression dynamics through a neural stochastic differential equation system within a variational autoencoder. Velvet outperforms current velocity tools across quantitative benchmarks, and predicts trajectory distributions that accurately recapitulate underlying dataset distributions while conserving known biology. Velvet trajectory distributions capture dynamical aspects such as decision boundaries between alternative fates and correlative gene regulatory structure. Using velvet to provide a dynamical description of in vitro neural patterning, we highlight a process of sequential decision making and fate-specific patterns of developmental signalling. Together, these experimental and computational methods recast single-cell analyses from descriptions of observed data distributions to models of the dynamics that generated them, providing a new framework for investigating developmental gene regulation and cell fate decisions.
2023-07-06 | GSE236517 | GEO
Project description:Developmental cell fate decisions are dynamic processes driven by the complex behaviour of gene regulatory networks. A challenge in studying these processes using single-cell genomics is that the data provides only a static snapshot with no detail of dynamics. Metabolic labelling and splicing can provide time-resolved information, but current methods have limitations. Here, we present experimental and computational methods that overcome these limitations to allow dynamical modelling of gene expression from single-cell data. We developed sci-FATE2, an optimised metabolic labelling method that substantially increases data quality, and profiled approximately 45,000 embryonic stem cells differentiating into multiple neural tube identities. To recover dynamics, we developed velvet, a deep learning framework that extends beyond instantaneous velocity estimation by modelling gene expression dynamics through a neural stochastic differential equation system within a variational autoencoder. Velvet outperforms current velocity tools across quantitative benchmarks, and predicts trajectory distributions that accurately recapitulate underlying dataset distributions while conserving known biology. Velvet trajectory distributions capture dynamical aspects such as decision boundaries between alternative fates and correlative gene regulatory structure. Using velvet to provide a dynamical description of in vitro neural patterning, we highlight a process of sequential decision making and fate-specific patterns of developmental signalling. Together, these experimental and computational methods recast single-cell analyses from descriptions of observed data distributions to models of the dynamics that generated them, providing a new framework for investigating developmental gene regulation and cell fate decisions.
2023-07-06 | GSE236512 | GEO