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Published on: April 2, 2018
An HLA-B regulatory element binds a factor immunologically related to the upstream stimulation factor
1MRC Laboratory of Molecular Biology, MRC Centre, Cambridge, UK.
Immunogenetics
|January 1, 1993
Summary
Researchers identified a novel regulatory element (R) in HLA-B gene expression. This element affects how interferon-stimulated genes (ISGs) are induced, impacting immune responses.
Area of Science:
- Immunogenetics
- Molecular Biology
- Gene Regulation
Background:
- Human Leukocyte Antigen (HLA)-A and -B genes are crucial for immune response and expressed in most cell types.
- Interferons (IFNs) significantly upregulate HLA-A and -B expression, with HLA-B loci showing stronger induction.
- Gene regulation involves specific DNA elements like enhancers (ENH) and interferon response elements (IREs) binding transcription factors (e.g., NF-κB, IRF).
Purpose of the Study:
- To identify and characterize novel regulatory elements involved in HLA-B gene induction by interferons.
- To elucidate the role of a newly discovered element ('R') in the differential regulation of HLA-A and HLA-B loci.
Main Methods:
- Identification of a novel regulatory element ('R') overlapping the interferon response element (IRE) in HLA-B loci.
- Analysis of the DNA binding activity of the 'R' element using nuclear extracts and specific antisera (anti-USF).
- Utilized reporter gene constructs to assess the functional impact of mutations within the 'R' element on IFN-alpha-induced gene expression.
Main Results:
- A novel regulatory element, 'R', containing a CACGAG core motif, was identified in the HLA-B promoter region, absent in HLA-A or H2 class I genes.
- The 'R' element binds a nuclear factor recognized by an antiserum against upstream stimulation factor (USF), a helix-loop-helix/leucine zipper protein.
- Mutation of the 'R' element led to increased IFN-alpha induction in certain cell lines, suggesting USF binding interferes with IRF-mediated induction.
Conclusions:
- The 'R' element plays a significant role in the differential interferon-gamma (IFN-γ) inducibility of HLA-B loci compared to HLA-A.
- USF binding to the 'R' element can modulate the interferon response, potentially through competitive binding with IRF proteins.
- This finding provides new insights into the complex regulatory mechanisms controlling HLA class I gene expression and immune cell function.
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