Dataset Information

Dynamic modeling of the cellular senescence gene regulatory network.

ABSTRACT: Cellular senescence is a cell fate that prominently impacts physiological and pathophysiological processes. Diverse cellular stresses induce it, and dramatic gene expression changes accompany it. However, determining the interactions comprising the gene regulatory network (GRN) governing senescence remains challenging. Recent advances in signal processing techniques provide opportunities to reconstruct GRNs. Here, we describe a GRN for senescence integrating time-series transcriptome and transcription factor depletion datasets. Specifically, we infer a set of differential equations using the "Sparse Identification of Nonlinear Dynamics" (SINDy) algorithm, discriminate genes with potential hidden regulators, validate the inferred GRN for time-points not included in the training data, and comprehensively benchmark our approach. Our work is a proof of concept for a data-driven GRN reconstruction method, consolidating an iterative, powerful mathematical platform for senescence modeling that can be used to test hypotheses in silico and has the potential for future discoveries of clinical impact.

SUBMITTER: Nabuco Leva Ferreira de Freitas JA

PROVIDER: S-EPMC10015196 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Dynamic modeling of the cellular senescence gene regulatory network.

Nabuco Leva Ferreira de Freitas José Américo JA Bischof Oliver O

Heliyon 20230225 3

Cellular senescence is a cell fate that prominently impacts physiological and pathophysiological processes. Diverse cellular stresses induce it, and dramatic gene expression changes accompany it. However, determining the interactions comprising the gene regulatory network (GRN) governing senescence remains challenging. Recent advances in signal processing techniques provide opportunities to reconstruct GRNs. Here, we describe a GRN for senescence integrating time-series transcriptome and transcr ...[more]

PMID: 36938415

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Project description:Gene regulation is a complicated process. The interaction of many genes and their products forms an intricate biological network. Identification of this dynamic network will help us understand the biological process in a systematic way. However, the construction of such a dynamic network is very challenging for a high-dimensional system. In this article we propose to use a set of ordinary differential equations (ODE), coupled with dimensional reduction by clustering and mixed-effects modeling techniques, to model the dynamic gene regulatory network (GRN). The ODE models allow us to quantify both positive and negative gene regulations as well as feedback effects of one set of genes in a functional module on the dynamic expression changes of the genes in another functional module, which results in a directed graph network. A five-step procedure, Clustering, Smoothing, regulation Identification, parameter Estimates refining and Function enrichment analysis (CSIEF) is developed to identify the ODE-based dynamic GRN. In the proposed CSIEF procedure, a series of cutting-edge statistical methods and techniques are employed, that include non-parametric mixed-effects models with a mixture distribution for clustering, nonparametric mixed-effects smoothing-based methods for ODE models, the smoothly clipped absolute deviation (SCAD)-based variable selection, and stochastic approximation EM (SAEM) approach for mixed-effects ODE model parameter estimation. The key step, the SCAD-based variable selection of the proposed procedure is justified by investigating its asymptotic properties and validated by Monte Carlo simulations. We apply the proposed method to identify the dynamic GRN for yeast cell cycle progression data. We are able to annotate the identified modules through function enrichment analyses. Some interesting biological findings are discussed. The proposed procedure is a promising tool for constructing a general dynamic GRN and more complicated dynamic networks.

Dataset Information

Dynamic modeling of the cellular senescence gene regulatory network.

Publications

Dynamic modeling of the cellular senescence gene regulatory network.

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