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Modular dynamics of DNA co-methylation networks exposes the functional organization of colon cancer cells’ genome

View ORCID ProfileIzaskun Mallona, Susanna Aussó, Anna Díez-Villanueva, View ORCID ProfileVíctor Moreno, View ORCID ProfileMiguel A. Peinado
doi: https://doi.org/10.1101/428730
Izaskun Mallona
1Health Research Institute Germans Trias i Pujol (IGTP), Program in Predictive and Personalized Medicine of Cancer. Badalona, Spain.
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  • For correspondence: mpeinado@igtp.cat izaskun.mallona@gmail.com
Susanna Aussó
2Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L’Hospitalet de Llobregat, Barcelona, Spain; Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
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Anna Díez-Villanueva
1Health Research Institute Germans Trias i Pujol (IGTP), Program in Predictive and Personalized Medicine of Cancer. Badalona, Spain.
2Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L’Hospitalet de Llobregat, Barcelona, Spain; Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
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Víctor Moreno
2Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L’Hospitalet de Llobregat, Barcelona, Spain; Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
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Miguel A. Peinado
1Health Research Institute Germans Trias i Pujol (IGTP), Program in Predictive and Personalized Medicine of Cancer. Badalona, Spain.
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  • For correspondence: mpeinado@igtp.cat izaskun.mallona@gmail.com
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Summary

DNA methylation dynamics is intrinsically interconnected with processes underlying the malignant properties of cancer cells. By applying network-based approaches in two series of colorectal cancers we dissected the long-range co-methylation structure finding consistent patterns of compartmentalization in both normal and tumor tissues. Large transchromosomal modules showed unique regulatory signatures and coalesced into a structured network and allowing simple patient stratification. Normal-tumor comparison revealed substantial remodeling of specific modules and migration of subsets of co-methylating sites denoted by functional aggregates, pointing out potential sources of epigenetic and phenotypic variability. We conclude that DNA methylation dynamics architecture embodies interpretable information that can be used as a proxy of the drivers and the phenotypes of malignant transformation.

Significance DNA methylation is a key epigenetic mark directly involved in genome organization and regulation. DNA methylation profiles are variable and are extensively altered in most cancers. We show that DNA methylation variability follows a transchromosomal modular dynamics in both normal and colon cancer cells. The reshaping of the DNA methylation variability network in tumorigenesis exposes genomic and functional associations and points out both the mechanisms and the phenotypes of individual tumors. This information may be used for patient stratification and identification of disrupted pathways and therapeutic targets.

Highlights

  • DNA methylation variability displays a modular architecture in normal and cancer.

  • Coordinated transchromosomal variations supersede regional DNA methylation dynamics.

  • Co-methylation network modularity evinces functional and structural features.

  • Epigenetic rewiring can be used as patient stratifier.

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Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 27, 2018.
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Modular dynamics of DNA co-methylation networks exposes the functional organization of colon cancer cells’ genome
Izaskun Mallona, Susanna Aussó, Anna Díez-Villanueva, Víctor Moreno, Miguel A. Peinado
bioRxiv 428730; doi: https://doi.org/10.1101/428730
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Modular dynamics of DNA co-methylation networks exposes the functional organization of colon cancer cells’ genome
Izaskun Mallona, Susanna Aussó, Anna Díez-Villanueva, Víctor Moreno, Miguel A. Peinado
bioRxiv 428730; doi: https://doi.org/10.1101/428730

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