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Human Molecular Genetics Advance Access published online on March 17, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh113
© 2004 by Oxford University Press
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©2004 Oxford University Press

Article

Polymorphisms at positions -22 and -348 in the promoter of the BAT1 gene affect transcription and the binding of nuclear factors

Patricia Price 1*, Agnes M-L. Wong 2, David Williamson 2, Dominic Voon 3, Svetlana Baltic 3, Richard J.N. Allcock 2, Alvin Boodhoo 4, and Frank T. Christiansen 2

1 School of Surgery and Pathology, University of Western Australia, Nedlands 6009, Australia; Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Wellington Street, Perth WA 6001, Australia
2 School of Surgery and Pathology, University of Western Australia, Nedlands 6009, Australia; Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth 6001, Australia
3 GeneStream Pty Ltd, Western Australia
4 Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth 6001, Australia; University of Mauritius, Reduit, Mauritius

* To whom correspondence should be addressed. E-mail: pprice{at}cyllene.uwa.edu.au.


  Abstract

BAT1 (D6S81E, UAP56) lies in the central MHC between TNF and HLA-B, a region containing genes that affect susceptibility to immunopathologic disorders. BAT1 protein may be directly responsible for the genetic association, as anti-sense studies show it can down-regulate inflammatory cytokines. Here we investigate polymorphisms at positions -22 and -348 relative to the BAT1 transcription start site. DNA samples from healthy donors were used to confirm haplotypic associations with the Type 1 diabetes-susceptible 8.1 ancestral haplotype (AH; HLA-A1,B8,BAT1-22*C,BAT1-348*C,DR3) and the diabetes-resistant 7.1AH (HLA-A3,B7,BAT1-22*G,BAT1-348*T,DR15). Alleles carried at BAT1-22 and -348 were in linkage disequilibrium.

Electrophoretic mobility shift assays using nuclear proteins from T-cells (Jurkat and HT2), monocytes (THP1, U937) and epithelial cells (HeLa and MDA468) demonstrated DNA:protein complexes binding oligonucleotides spanning positions -22 and -348 on the 7.1AH only. Competition assays, supershifts and molecular weight determinations suggest the complexes include the transcription factors YY1 (at -348) and Oct1 (at -22).

Promoter activity was demonstrated using 520bp and 336bp fragments cloned from immediately upstream of the transcription start site and carrying all combinations of -22 and -348 alleles, suggesting an unidentified non-polymorphic sequence within 336bp of the start site drives transcription. The 520bp fragment of the BAT1 promoter cloned from the 8.1AH was slightly less efficient than the equivalent from the 7.1AH, whilst the reverse was observed with 336bp fragments. This suggests BAT1 transcription on the 7.1AH is modified by interactions involving DNA flanking positions -22 and -348.


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