Epigenetically driven network cooperativity: Meta-analysis in multi-drug resistant osteosarcoma

Antonio Mora, Monia Taranta, Nazar Zaki, Caterina Cinti, Enrico Capobianco

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Osteosarcoma (OS) pathogenesis is not yet clear in terms of cellular network architecture, likewise the understanding of genetic regulatory mechanisms and epigenetic interplay between DNA methylation and histone modification processes. We aim to assess the epigenetic influences on gene expression in the multi-drug resistant OS HosDXR150 cell line after administration of DNA methyltransferases and histone deacetylases inhibitors separately and in combination. A network inference approach is proposed to integrate the signal variation from differentially expressed (DE) genes with the connectivity patterns underlying protein-protein interactions with the aim of investigating modular aggregates and assign significance to them in view of validation. Identifications of novel network entities emerge from cohesive functional modules that cooperate to accomplish mediation between cancer phenotypes. These 'network sentinels' are topologically characterized and computed to reveal synergies between driver and DE genes, thus refining the evaluation of cross-linked pathway relationships and the accurate selection of targets. We demonstrate the utility of network-functionalized assessment of connected OS phenotypes, emphasizing two main observed features: (i) the differential spatial localization between single and combined epigenetic treatments in terms of network propagation of their variation effects and (ii) the controllability role played by specialized modules mediating the observed variation. While epigenetic regulation of cancer remains quite a hurdle, we stress the utility of inference based on integrative network approaches, and shed light on the mediation processes between complex phenotypes and regulatory circuits triggered by epigenetic treatments.

Original languageEnglish (US)
Pages (from-to)296-317
Number of pages22
JournalJournal of Complex Networks
Volume4
Issue number2
DOIs
StatePublished - Jun 2016

Keywords

  • Epigenetic treatments
  • Gene expression
  • Network inference
  • Osteosarcoma

ASJC Scopus subject areas

  • Computer Networks and Communications
  • Management Science and Operations Research
  • Control and Optimization
  • Computational Mathematics
  • Applied Mathematics

Fingerprint

Dive into the research topics of 'Epigenetically driven network cooperativity: Meta-analysis in multi-drug resistant osteosarcoma'. Together they form a unique fingerprint.

Cite this