OR19 MIRNA mediated post transcriptional regulation of HLA transcripts

Abstract

Aim MicroRNAs (miRNAs) regulate the post-transcriptional expression of targeted mRNA transcripts, however little is known about the influence of HLA polymorphisms on altered miRNA target specificity & allele specific post-transcriptional regulation. We utilize a custom developed bioinformatics platform, utilizing both miRNA transcript expression data and computational miRNA target site prediction to study the influence of HLA polymorphisms on altered miRNA target specificity and differential post-transcriptional regulation of HLA alleles within B and T lymphocytes. Methods Computational predicted miRNA target sites for all known miRNA transcripts (miRBase release 21) within the 3 ′ UTR of every known full-length HLA allele for HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DPB1 and HLA-DRB1 (IMGT version 3.27) were determined using miRanda with a minimum heteroduplex energy of −20 Kcal/mol. Tissue specific miRNA expression profiles were subsequently used to filter miRNA-target interactions in order to determine the tissue specific differential miRNA target specificity HLA alleles. Results Our data demonstrate that endogenously expressed miRNA within both B and T lymphocytes display differential target specificity across HLA alleles, driven by polymorphisms present within the 3 ′ UTR of HLA alleles. Interestingly, we find differential targeting of endogenously expressed miRNA within polymorphic regions of HLA-DRB1 and HLA-G that have been associated with altered HLA expression and implicated in GVHD, preeclampsia, oncogenesis and allograft rejection. We also observe that several endogenously expressed miRNAs target the 3 ′ UTR of numerous HLA genes, acting as a potential master, universal regulator of HLA expression with B and T lymphocytes. Conclusions The developed bioinformatics platform identifies target sites of all known miRNA on the 3 ′ UTR of every annotated full-length HLA allele. This atlas is further refined using tissue specific miRNA expression patterns to generate tissue specific target maps, revealing altered miRNA target specificity both across tissue types and across HLA alleles, driven by polymorphisms across HLA alleles. This powerful platform may be used to test novel hypothesis related to altered HLA expression as it relates to a variety of disease states.