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Inferring latent temporal progression and regulatory networks from cross-sectional transcriptomic data of cancer samples

Unraveling molecular regulatory networks underlying disease progression is critically important for understanding disease mechanisms and identifying drug targets. The existing methods for inferring gene regulatory networks (GRNs) rely mainly on time-course gene expression data. However, most availab...

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Detalles Bibliográficos
Autores principales: Sun, Xiaoqiang, Zhang, Ji, Nie, Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968745/
https://www.ncbi.nlm.nih.gov/pubmed/33667222
http://dx.doi.org/10.1371/journal.pcbi.1008379
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author Sun, Xiaoqiang
Zhang, Ji
Nie, Qing
author_facet Sun, Xiaoqiang
Zhang, Ji
Nie, Qing
author_sort Sun, Xiaoqiang
collection PubMed
description Unraveling molecular regulatory networks underlying disease progression is critically important for understanding disease mechanisms and identifying drug targets. The existing methods for inferring gene regulatory networks (GRNs) rely mainly on time-course gene expression data. However, most available omics data from cross-sectional studies of cancer patients often lack sufficient temporal information, leading to a key challenge for GRN inference. Through quantifying the latent progression using random walks-based manifold distance, we propose a latent-temporal progression-based Bayesian method, PROB, for inferring GRNs from the cross-sectional transcriptomic data of tumor samples. The robustness of PROB to the measurement variabilities in the data is mathematically proved and numerically verified. Performance evaluation on real data indicates that PROB outperforms other methods in both pseudotime inference and GRN inference. Applications to bladder cancer and breast cancer demonstrate that our method is effective to identify key regulators of cancer progression or drug targets. The identified ACSS1 is experimentally validated to promote epithelial-to-mesenchymal transition of bladder cancer cells, and the predicted FOXM1-targets interactions are verified and are predictive of relapse in breast cancer. Our study suggests new effective ways to clinical transcriptomic data modeling for characterizing cancer progression and facilitates the translation of regulatory network-based approaches into precision medicine.
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spelling pubmed-79687452021-03-31 Inferring latent temporal progression and regulatory networks from cross-sectional transcriptomic data of cancer samples Sun, Xiaoqiang Zhang, Ji Nie, Qing PLoS Comput Biol Research Article Unraveling molecular regulatory networks underlying disease progression is critically important for understanding disease mechanisms and identifying drug targets. The existing methods for inferring gene regulatory networks (GRNs) rely mainly on time-course gene expression data. However, most available omics data from cross-sectional studies of cancer patients often lack sufficient temporal information, leading to a key challenge for GRN inference. Through quantifying the latent progression using random walks-based manifold distance, we propose a latent-temporal progression-based Bayesian method, PROB, for inferring GRNs from the cross-sectional transcriptomic data of tumor samples. The robustness of PROB to the measurement variabilities in the data is mathematically proved and numerically verified. Performance evaluation on real data indicates that PROB outperforms other methods in both pseudotime inference and GRN inference. Applications to bladder cancer and breast cancer demonstrate that our method is effective to identify key regulators of cancer progression or drug targets. The identified ACSS1 is experimentally validated to promote epithelial-to-mesenchymal transition of bladder cancer cells, and the predicted FOXM1-targets interactions are verified and are predictive of relapse in breast cancer. Our study suggests new effective ways to clinical transcriptomic data modeling for characterizing cancer progression and facilitates the translation of regulatory network-based approaches into precision medicine. Public Library of Science 2021-03-05 /pmc/articles/PMC7968745/ /pubmed/33667222 http://dx.doi.org/10.1371/journal.pcbi.1008379 Text en © 2021 Sun et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sun, Xiaoqiang
Zhang, Ji
Nie, Qing
Inferring latent temporal progression and regulatory networks from cross-sectional transcriptomic data of cancer samples
title Inferring latent temporal progression and regulatory networks from cross-sectional transcriptomic data of cancer samples
title_full Inferring latent temporal progression and regulatory networks from cross-sectional transcriptomic data of cancer samples
title_fullStr Inferring latent temporal progression and regulatory networks from cross-sectional transcriptomic data of cancer samples
title_full_unstemmed Inferring latent temporal progression and regulatory networks from cross-sectional transcriptomic data of cancer samples
title_short Inferring latent temporal progression and regulatory networks from cross-sectional transcriptomic data of cancer samples
title_sort inferring latent temporal progression and regulatory networks from cross-sectional transcriptomic data of cancer samples
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968745/
https://www.ncbi.nlm.nih.gov/pubmed/33667222
http://dx.doi.org/10.1371/journal.pcbi.1008379
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