Temporal Profiling of Cytokine-Induced Genes in Pancreatic β-cells by Meta-Analysis and Network Inference

Genomics. 2014 Apr;103(4):264-75. doi: 10.1016/j.ygeno.2013.12.007. Epub 2014 Jan 24.

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.

Keywords: Cytokines; Diabetes; Gene expression; Meta-analysis; Network inference; Pancreatic beta cells; Time series.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism*
  • Cytokines / pharmacology
  • DNA-Binding Proteins / genetics
  • Diabetes Mellitus, Type 1
  • Gene Expression Profiling / methods*
  • Gene Regulatory Networks*
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology
  • Islets of Langerhans / physiology
  • Proto-Oncogene Proteins c-ets / genetics
  • Rats
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / genetics
  • Reproducibility of Results
  • Transcription Factors / genetics

Substances

  • Cytokines
  • DNA-Binding Proteins
  • ELF3 protein, human
  • Proto-Oncogene Proteins c-ets
  • Transcription Factors
  • Interferon-gamma
  • RIPK2 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinase 2

Associated data

  • GEO/GSE53453
  • GEO/GSE53454