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cAMP-responsive element modulator α (CREMα) contributes to decreased Notch-1 expression in T cells from patients with

Thomas Rauen1, Alexandros P Grammatikos, Christian M Hedrich

  • 1Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.

The Journal of Biological Chemistry
|November 6, 2012
PubMed

Insights

Notch-1 expression is reduced in T cells of systemic lupus erythematosus (SLE) patients due to epigenetic changes. This dysregulation, involving CREMα, impacts T cell function and disease activity.

Area of Science:

  • Immunology
  • Molecular Biology
  • Epigenetics

Background:

  • Notch signaling is crucial for cell decisions and T cell development.
  • T cells in systemic lupus erythematosus (SLE) exhibit aberrant phenotypes, including impaired Notch-1 receptor expression.
  • Understanding Notch-1 regulation in SLE is vital for elucidating disease mechanisms.

Purpose of the Study:

  • To investigate the mechanisms underlying decreased Notch-1 expression in T cells from SLE patients.
  • To explore the role of epigenetic modifications and CREMα in Notch-1 dysregulation in SLE.
  • To assess the correlation between Notch-1 levels, disease activity, and IL-17A in SLE.

Main Methods:

  • Quantification of Notch-1 mRNA and protein levels in T cells from SLE patients.
  • Analysis of histone H3 and CpG DNA methylation at the Notch-1 promoter.
  • Chromatin immunoprecipitation assays to assess CREMα binding to the Notch-1 promoter.
  • Measurement of IL-17A levels in relation to Notch-1 expression.

Main Results:

  • Basal Notch-1 expression is significantly decreased in T cells from active SLE patients.
  • Decreased Notch-1 expression correlates inversely with SLE disease activity.
  • Enhanced histone H3 and CpG DNA methylation, along with increased CREMα binding, contribute to reduced Notch-1 promoter activity and transcription.
  • Lower Notch-1 levels are associated with elevated IL-17A levels.

Conclusions:

  • Epigenetic dysregulation, including DNA and histone methylation, mediated by CREMα, underlies reduced Notch-1 expression in SLE T cells.
  • Notch-1 plays a significant role in the immunopathogenesis of SLE.
  • These findings reveal novel molecular mechanisms contributing to aberrant T cell function in SLE.

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