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Molecular mechanisms for synchronized transcription of three complement C1q subunit genes in dendritic cells and

Guobao Chen1, Carol Shurong Tan, Boon King Teh

  • 1Department of Microbiology, Yong Loo Lin School of Medicine and Immunology Programme, National University of Singapore, Block MD4, 5 Science Drive 2, Singapore 117597.

The Journal of Biological Chemistry
|August 25, 2011
PubMed

Insights

Complement component 1q (C1q) gene expression synchronization is crucial for preventing systemic lupus erythematosus. This study uncovers a novel transcriptional mechanism involving PU.1 and IRF8, explaining how C1q gene expression is coordinated.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Hereditary C1q deficiency is rare but strongly linked to systemic lupus erythematosus (SLE).
  • C1q levels can decrease in SLE patients without genetic defects, suggesting complex regulation of C1q production.
  • C1q is an 18-subunit protein assembled from three distinct genes (C1qA, C1qC, C1qB) located on chromosome 1, with synchronized expression.

Purpose of the Study:

  • To investigate the transcriptional mechanisms regulating the synchronized expression of the three human C1q genes.
  • To identify transcription factors and regulatory elements involved in C1q gene expression, particularly in response to IFNγ.

Main Methods:

  • Cloning and functional analysis of the three human C1q gene promoters using luciferase reporter assays.
  • Investigating the role of a specific 53-bp element in the C1qB promoter.
  • Chromatin immunoprecipitation (ChIP) to identify transcription factor binding.
  • shRNA knockdown experiments to assess the function of PU.1 and IRF8.
  • Exploring the role of STAT1 in regulating C1qB promoter activity.

Main Results:

  • The C1qB promoter showed expected basal and IFNγ-stimulated activity, while C1qA and C1qC promoters were suppressed by IFNγ.
  • A 53-bp element in the C1qB promoter was essential for its activity.
  • Transcription factors PU.1 and IRF8 were identified as binding to this essential element.
  • Knockdown of PU.1 and IRF8 reduced the C1qB promoter's response to IFNγ.
  • STAT1 regulated the C1qB promoter via IRF8 induction.

Conclusions:

  • A novel transcriptional mechanism synchronizes the expression of the three C1q genes.
  • PU.1 and IRF8 binding to a key element in the C1qB promoter are critical for IFNγ-mediated regulation and coordinated gene expression.
  • Understanding this mechanism provides insights into C1q deficiency and its role in systemic lupus erythematosus pathogenesis.

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