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SUBATOMIC: a SUbgraph BAsed mulTi-OMIcs clustering framework to analyze integrated multi-edge networks

BACKGROUND: Representing the complex interplay between different types of biomolecules across different omics layers in multi-omics networks bears great potential to gain a deep mechanistic understanding of gene regulation and disease. However, multi-omics networks easily grow into giant hairball st...

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Autores principales: Loers, Jens Uwe, Vermeirssen, Vanessa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9442970/
https://www.ncbi.nlm.nih.gov/pubmed/36064320
http://dx.doi.org/10.1186/s12859-022-04908-3
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author Loers, Jens Uwe
Vermeirssen, Vanessa
author_facet Loers, Jens Uwe
Vermeirssen, Vanessa
author_sort Loers, Jens Uwe
collection PubMed
description BACKGROUND: Representing the complex interplay between different types of biomolecules across different omics layers in multi-omics networks bears great potential to gain a deep mechanistic understanding of gene regulation and disease. However, multi-omics networks easily grow into giant hairball structures that hamper biological interpretation. Module detection methods can decompose these networks into smaller interpretable modules. However, these methods are not adapted to deal with multi-omics data nor consider topological features. When deriving very large modules or ignoring the broader network context, interpretability remains limited. To address these issues, we developed a SUbgraph BAsed mulTi-OMIcs Clustering framework (SUBATOMIC), which infers small and interpretable modules with a specific topology while keeping track of connections to other modules and regulators. RESULTS: SUBATOMIC groups specific molecular interactions in composite network subgraphs of two and three nodes and clusters them into topological modules. These are functionally annotated, visualized and overlaid with expression profiles to go from static to dynamic modules. To preserve the larger network context, SUBATOMIC investigates statistically the connections in between modules as well as between modules and regulators such as miRNAs and transcription factors. We applied SUBATOMIC to analyze a composite Homo sapiens network containing transcription factor-target gene, miRNA-target gene, protein–protein, homologous and co-functional interactions from different databases. We derived and annotated 5586 modules with diverse topological, functional and regulatory properties. We created novel functional hypotheses for unannotated genes. Furthermore, we integrated modules with condition specific expression data to study the influence of hypoxia in three cancer cell lines. We developed two prioritization strategies to identify the most relevant modules in specific biological contexts: one considering GO term enrichments and one calculating an activity score reflecting the degree of differential expression. Both strategies yielded modules specifically reacting to low oxygen levels. CONCLUSIONS: We developed the SUBATOMIC framework that generates interpretable modules from integrated multi-omics networks and applied it to hypoxia in cancer. SUBATOMIC can infer and contextualize modules, explore condition or disease specific modules, identify regulators and functionally related modules, and derive novel gene functions for uncharacterized genes. The software is available at https://github.com/CBIGR/SUBATOMIC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12859-022-04908-3.
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spelling pubmed-94429702022-09-06 SUBATOMIC: a SUbgraph BAsed mulTi-OMIcs clustering framework to analyze integrated multi-edge networks Loers, Jens Uwe Vermeirssen, Vanessa BMC Bioinformatics Research BACKGROUND: Representing the complex interplay between different types of biomolecules across different omics layers in multi-omics networks bears great potential to gain a deep mechanistic understanding of gene regulation and disease. However, multi-omics networks easily grow into giant hairball structures that hamper biological interpretation. Module detection methods can decompose these networks into smaller interpretable modules. However, these methods are not adapted to deal with multi-omics data nor consider topological features. When deriving very large modules or ignoring the broader network context, interpretability remains limited. To address these issues, we developed a SUbgraph BAsed mulTi-OMIcs Clustering framework (SUBATOMIC), which infers small and interpretable modules with a specific topology while keeping track of connections to other modules and regulators. RESULTS: SUBATOMIC groups specific molecular interactions in composite network subgraphs of two and three nodes and clusters them into topological modules. These are functionally annotated, visualized and overlaid with expression profiles to go from static to dynamic modules. To preserve the larger network context, SUBATOMIC investigates statistically the connections in between modules as well as between modules and regulators such as miRNAs and transcription factors. We applied SUBATOMIC to analyze a composite Homo sapiens network containing transcription factor-target gene, miRNA-target gene, protein–protein, homologous and co-functional interactions from different databases. We derived and annotated 5586 modules with diverse topological, functional and regulatory properties. We created novel functional hypotheses for unannotated genes. Furthermore, we integrated modules with condition specific expression data to study the influence of hypoxia in three cancer cell lines. We developed two prioritization strategies to identify the most relevant modules in specific biological contexts: one considering GO term enrichments and one calculating an activity score reflecting the degree of differential expression. Both strategies yielded modules specifically reacting to low oxygen levels. CONCLUSIONS: We developed the SUBATOMIC framework that generates interpretable modules from integrated multi-omics networks and applied it to hypoxia in cancer. SUBATOMIC can infer and contextualize modules, explore condition or disease specific modules, identify regulators and functionally related modules, and derive novel gene functions for uncharacterized genes. The software is available at https://github.com/CBIGR/SUBATOMIC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12859-022-04908-3. BioMed Central 2022-09-05 /pmc/articles/PMC9442970/ /pubmed/36064320 http://dx.doi.org/10.1186/s12859-022-04908-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Loers, Jens Uwe
Vermeirssen, Vanessa
SUBATOMIC: a SUbgraph BAsed mulTi-OMIcs clustering framework to analyze integrated multi-edge networks
title SUBATOMIC: a SUbgraph BAsed mulTi-OMIcs clustering framework to analyze integrated multi-edge networks
title_full SUBATOMIC: a SUbgraph BAsed mulTi-OMIcs clustering framework to analyze integrated multi-edge networks
title_fullStr SUBATOMIC: a SUbgraph BAsed mulTi-OMIcs clustering framework to analyze integrated multi-edge networks
title_full_unstemmed SUBATOMIC: a SUbgraph BAsed mulTi-OMIcs clustering framework to analyze integrated multi-edge networks
title_short SUBATOMIC: a SUbgraph BAsed mulTi-OMIcs clustering framework to analyze integrated multi-edge networks
title_sort subatomic: a subgraph based multi-omics clustering framework to analyze integrated multi-edge networks
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9442970/
https://www.ncbi.nlm.nih.gov/pubmed/36064320
http://dx.doi.org/10.1186/s12859-022-04908-3
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