Temporal profiling of cytokine-induced genes in pancreatic β-cells by meta-analysis and network inference

Miguel Lopes, Burak Kutlu, Michela Miani, Claus Heiner Bang-Berthelsen, Joachim Størling, Flemming Pociot, Nathan Goodman, Lee Hood, Nils Welsh, Gianluca Bontempi, Decio L. Eizirik

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Type 1 Diabetes (T1D) is an autoimmune disease where local release of cytokines such as IL-1β and IFN-γ contributes to β-cell apoptosis. To identify relevant genes regulating this process we performed a meta-analysis of 8 datasets of β-cell gene expression after exposure to IL-1β and IFN-γ. Two of these datasets are novel and contain time-series expressions in human islet cells and rat INS-1E cells. Genes were ranked according to their differential expression within and after 24. h from exposure, and characterized by function and prior knowledge in the literature. A regulatory network was then inferred from the human time expression datasets, using a time-series extension of a network inference method. The two most differentially expressed genes previously unknown in T1D literature (RIPK2 and ELF3) were found to modulate cytokine-induced apoptosis. The inferred regulatory network is thus supported by the experimental validation, providing a proof-of-concept for the proposed statistical inference approach. © 2014 Elsevier Inc.
Original languageEnglish
JournalGenomics
Volume103
Issue number4
Pages (from-to)264-275
Number of pages12
ISSN0888-7543
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Genetics
  • Medicine (all)
  • Cytokines
  • Diabetes
  • Gene expression
  • Meta-analysis
  • Network inference
  • Pancreatic beta cells
  • Time series
  • gamma interferon
  • gamma interferon receptor 1
  • interleukin 1 receptor
  • interleukin 1beta
  • cytokine
  • DNA binding protein
  • ELF3 protein, human
  • receptor interacting protein serine threonine kinase 2
  • RIPK2 protein, human
  • transcription factor
  • transcription factor Ets
  • animal cell
  • apoptosis
  • article
  • controlled study
  • cytokine production
  • down regulation
  • ELF3 gene
  • gene
  • gene expression profiling
  • gene expression regulation
  • human
  • human cell
  • insulin dependent diabetes mellitus
  • microarray analysis
  • nonhuman
  • nucleotide sequence
  • pancreas islet beta cell
  • priority journal
  • rat
  • RIPK2 gene
  • RNA sequence
  • upregulation
  • validation process
  • animal
  • drug effects
  • gene regulatory network
  • genetics
  • meta analysis
  • metabolism
  • pancreas islet
  • physiology
  • procedures
  • reproducibility
  • Animals
  • Diabetes Mellitus, Type 1
  • DNA-Binding Proteins
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Humans
  • Insulin-Secreting Cells
  • Interferon-gamma
  • Islets of Langerhans
  • Proto-Oncogene Proteins c-ets
  • Rats
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Reproducibility of Results
  • Transcription Factors
  • Cytology - Animal
  • Cytology - Human
  • Genetics - General
  • Genetics - Animal
  • Genetics - Human
  • Mathematical biology and statistical methods
  • Biochemistry studies - Nucleic acids, purines and pyrimidines
  • Biochemistry studies - Proteins, peptides and amino acids
  • Metabolism - General metabolism and metabolic pathways
  • Metabolism - Metabolic disorders
  • Endocrine - General
  • Endocrine - Pancreas
  • Immunology - General and methods
  • Immunology - Immunopathology, tissue immunology
  • Animals, Chordates, Humans, Mammals, Primates, Vertebrates
  • Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates

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