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Coordinated regulation of IFITM1, 2 and 3 genes by an IFN-responsive enhancer through long-range chromatin

Ping Li1, Ming-Lei Shi1, Wen-Long Shen1

  • 1Beijing Institute of Biotechnology, No. 20, Dongdajie Street, Fengtai District, Beijing 100071, China.

Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms
|May 18, 2017
PubMed

Insights

A newly discovered enhancer regulates interferon-induced transmembrane protein (IFITM) 1, 2, and 3 genes. This enhancer, bound by STAT1, is crucial for antiviral defense against influenza A virus (IAV).

Area of Science:

  • Molecular Biology
  • Immunology
  • Virology

Background:

  • Interferon-induced transmembrane proteins (IFITMs) 1, 2, and 3 are key in blocking pathogen entry.
  • Transcriptional regulation and enhancers of IFITM genes during interferon (IFN) induction are not well understood.

Purpose of the Study:

  • To identify and characterize regulatory elements controlling IFITM1, IFITM2, and IFITM3 gene expression.
  • To elucidate the role of these elements in the interferon response and antiviral immunity.

Main Methods:

  • Public data mining
  • Episomal luciferase reporter assays
  • CRISPR-Cas9 genome editing
  • Chromatin immunoprecipitation (ChIP)
  • Electrophoretic mobility shift assay (EMSA)
  • Chromosome conformation capture (3C)
  • Influenza A virus (IAV) infection models.

Main Results:

  • An IFN-responsive enhancer located 35kb upstream of the IFITM3 promoter was identified, upregulating IFITM1, 2, and 3 expression.
  • Signal transducer and activator of transcription 1 (STAT1) binds to this enhancer upon IFN treatment, mediating its activity.
  • IFITM1, 2, and 3 genes form physical clusters that loop to the distal enhancer, enabling coordinated regulation.
  • In vivo disruption of the enhancer reduced IFN-induced resistance to IAV infection.

Conclusions:

  • A distal enhancer plays a critical role in the coordinated, IFN-induced transcriptional regulation of IFITM1, 2, and 3.
  • This enhancer-gene interaction is essential for mediating antiviral responses, specifically against influenza A virus.
  • Findings provide insights into the molecular mechanisms of interferon signaling and IFITM-mediated immunity.
Keywords:
EnhancerIFITMIFNInfluenza A virusLong-range interactions

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