Autoimmune vitiligo is associated with gain-of-function by a transcriptional regulator that elevates expression of HLA-A02:01 in vivo

Autoimmune vitiligo is associated with gain-of-function by a transcriptional regulator that elevates expression of HLA-A02:01 in vivo

HLA-A is a class I major histocompatibility complex receptor that presents peptide antigens on the surface of most cells. Vitiligo, an autoimmune disease in which skin melanocytes are destroyed by cognate T cells, is associated with variation in the HLA-A gene; specifically HLA-A*02:01, which presen...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2016-02, Vol.113 (5), p.1357-1362
Main Authors: Hayashi, Masahiro, Jin, Ying, Yorgov, Daniel, Santorico, Stephanie A., Hagman, James, Ferrara, Tracey M., Jones, Kenneth L., Cavalli, Giulio, Dinarello, Charles A., Spritz, Richard A.
Format: Article
Language:eng
Subjects:
Autoimmune Diseases - genetics
Autoimmune Diseases - immunology
Biological Sciences
Gene expression
Gene Expression Regulation
Haplotypes
HLA-A Antigens - genetics
Humans
Plastids
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Ribonucleic acid
RNA
Transcription factors
Transcription, Genetic
Vitiligo
Vitiligo - genetics
Vitiligo - immunology
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Summary:HLA-A is a class I major histocompatibility complex receptor that presents peptide antigens on the surface of most cells. Vitiligo, an autoimmune disease in which skin melanocytes are destroyed by cognate T cells, is associated with variation in the HLA-A gene; specifically HLA-A*02:01, which presents multiple vitiligo melanocyte autoantigens. Refined genetic mapping localizes vitiligo risk in the HLA-A region to an SNP haplotype ∼20-kb downstream, spanning an ENCODE element with many characteristics of a transcriptional enhancer. Convergent CTCF insulator sites flanking the HLA-A gene promoter and the predicted transcriptional regulator, with apparent interaction between these sites, suggests this element regulates the HLA-A promoter. Peripheral blood mononuclear cells from healthy subjects homozygous for the high-risk haplotype expressed 39% more HLA-A RNA than cells from subjects carrying nonhigh-risk haplotypes (P = 0.0048). Similarly, RNAseq analysis of 1,000 Genomes Project data showed more HLA-A mRNA expressed in subjects homozygous for the high-risk allele of lead SNP rs60131261 than subjects homozygous for the low-risk allele (P = 0.006). Reporter plasmid transfection and genomic run-on sequence analyses confirm that the HLA-A transcriptional regulator contains multiple bidirectional promoters, with greatest activity on the high-risk haplotype, although it does not behave as a classic enhancer. Vitiligo risk associated with the MHC class I region thus derives from combined quantitative and qualitative phenomena: a SNP haplotype in a transcriptional regulator that induces gainof-function, elevating expression of HLA-A RNA in vivo, in strong linkage disequilibrium with an HLA-A allele that confers *02:01 specificity.
ISSN:0027-8424
1091-6490