Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

Raj, Prithvi; Rai, Ekta; Song, Ran; Khan, Shaheen; Wakeland, Benjamin; Viswanathan, Kasthuribai; Arana, Carlos; Liang, Chao; Zhang, Bo; Dozmorov, Igor; Carr-Johnson, Ferdicia; Mitrovič, Mitja; Wiley, Graham B.; Kelly, Jennifer A.; Lauwerys, Bernard; Olsen, Nancy J.; Cotsapas, Chris; Garcia, Christine Kim; Wise, Carol A.; Harley, John B.; Nath, Swapan K.; James, Judith A.; Jacob, Chaim O.; Tsao, Betty P.; Pasare, Chandrashekhar; Karp, David R.; Li, Quan Zhen; Gaffney, Patrick M.; Wakeland, Edward K.

doi:10.7554/elife.12089

Cited by 119 publications

(110 citation statements)

References 138 publications

(162 reference statements)

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“…This effect of Stat4 may be independent of its roles in promoting IFN-γ production, although further studies are needed to confirm this. Recent data show that a lupus-associated SNP in the STAT4 gene leads to increased Stat4 expression (114), supporting the idea that higher Stat4 expression may promote autoimmunity. Interestingly, knockout of the Stat4 gene reduces autoantibody production in lupus-prone B6.TC mice (115).…”

Section: Discussionmentioning

confidence: 75%

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1

et al. 2017

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BackgroundThe transcription factor Ets1 is highly expressed in B lymphocytes. Loss of Ets1 leads to premature B cell differentiation into antibody-secreting cells (ASCs), secretion of autoantibodies, and development of autoimmune disease. Despite the importance of Ets1 in B cell biology, few Ets1 target genes are known in these cells.ResultsTo obtain a more complete picture of the function of Ets1 in regulating B cell differentiation, we performed Ets1 ChIP-seq in primary mouse B cells to identify >10,000-binding sites, many of which were localized near genes that play important roles in B cell activation and differentiation. Although Ets1 bound to many sites in the genome, it was required for regulation of less than 5% of them as evidenced by gene expression changes in B cells lacking Ets1. The cohort of genes whose expression was altered included numerous genes that have been associated with autoimmune disease susceptibility. We focused our attention on four such Ets1 target genes Ptpn22, Stat4, Egr1, and Prdm1 to assess how they might contribute to Ets1 function in limiting ASC formation. We found that dysregulation of these particular targets cannot explain altered ASC differentiation in the absence of Ets1.ConclusionWe have identified genome-wide binding targets for Ets1 in B cells and determined that a relatively small number of these putative target genes require Ets1 for their normal expression. Interestingly, a cohort of genes associated with autoimmune disease susceptibility is among those that are regulated by Ets1. Identification of the target genes of Ets1 in B cells will help provide a clearer picture of how Ets1 regulates B cell responses and how its loss promotes autoantibody secretion.

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Section: Discussionmentioning

confidence: 75%

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1

et al. 2017

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“…Differential HLA expression levels have been associated with infectious (60–63), autoimmune and inflammatory (61, 64–67) disease outcome. Our data indicate that alternative polyadenylation is one mechanism by which HLA-A cell surface expression levels are regulated, potentially affecting HLA-A-mediated immune responses.…”

Section: Discussionmentioning

confidence: 99%

Posttranscriptional Regulation of HLA-A Protein Expression by Alternative Polyadenylation Signals Involving the RNA-Binding Protein Syncrip

Kulkarni

Ramsuran

Ručević

et al. 2017

The Journal of Immunology

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Genomic variation in the untranslated region (UTR) has been shown to influence human leukocyte antigen (HLA) class I expression level, and associate with disease outcomes. Sequencing of the 3’UTR of common HLA-A alleles indicated the presence of two polyadenylation signals (PAS). The proximal PAS is conserved, whereas the distal PAS is disrupted within certain alleles by sequence variants. Using 3’ rapid amplification of cDNA ends (3’RACE), we confirmed expression of two distinct forms of the HLA-A 3’UTR based on use of either the proximal or the distal PAS, which differ in length by 100 base pairs. Specific HLA-A alleles varied in the usage of the proximal vs. distal PAS, with some alleles using only the proximal, and others using both the proximal and distal PAS to differing degrees. We show that the short and the long 3’UTR produced similar mRNA expression levels. However, the long 3’UTR conferred lower luciferase activity as compared to the short form, indicating translation inhibition of the long 3’UTR. RNA affinity pull down followed by mass spectrometry (MS) analysis as well as RNA co-immunoprecipitation indicated differential binding of Syncrip to the long vs. short 3’UTR. Depletion of Syncrip by siRNA increased surface expression of an HLA-A allotype that uses primarily the long 3’UTR, whereas an allotype expressing only the short form was unaffected. Further, specific blocking of the proximal 3’UTR reduced surface expression without decreasing mRNA expression. These data demonstrate HLA-A allele-specific variation in PAS usage, which modulates their cell surface expression post-transcriptionally.

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“…Several studies have indicated that expression levels of certain HLA loci vary in an allotype dependent manner (4–16) and this variation has been shown to associate with certain diseases, such as outcome after HIV infection (4, 17), Crohn’s disease (4), HBV clearance (8), graft-versus-host disease after unrelated hematopoietic cell transplantation (18, 19), Parkinson’s disease (20), systemic lupus erythematosus (21) and certain cancers (22–24). The regulation of HLA class I expression is mediated by a series of core promoter motifs, which are located within 500 bp upstream of the start site and are relatively conserved (25).…”

Section: Introductionmentioning

confidence: 99%

Sequence and Phylogenetic Analysis of the Untranslated Promoter Regions for HLA Class I Genes

Ramsuran

Hernandez-Sanchez

Ó'hUigín

et al. 2017

The Journal of Immunology

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Polymorphisms located within the MHC have been linked to many disease outcomes by mechanisms not yet fully understood in most cases. Variants located within untranslated regions of HLA genes are involved in allele specific expression and may therefore underlie some of these disease associations. We determined sequences extending nearly 2kb upstream of the transcription start site for 68 alleles from 57 major lineages of classical HLA class I genes. The nucleotide diversity within this promoter segment roughly follows that seen within the coding regions, with HLA-B showing the highest (~1.9%), followed by HLA–A (~1.8%), and HLA–C showing the lowest diversity (~0.9%). In spite of its greater diversity, HLA-B mRNA expression levels determined in 178 European Americans do not vary in an allele- or lineage-specific manner, unlike the differential expression levels of HLA-A or HLA-C reported previously. Close proximity of promoter sequences in phylogenetic trees is roughly reflected by similarity of expression pattern for most HLA-A and -C loci. While promoter sequence divergence might impact promoter activity, we observed no clear link between the phylogenetic structure as represented by pairwise nucleotide differences in the promoter regions with estimated differences in mRNA expression levels for the classical class I loci. Further, no pair of class I loci showed coordinated expression levels, suggesting that distinct mechanisms across loci determine their expression level under non-stimulated conditions. These data serve as a foundation for more in depth analysis of the functional consequences of promoter region variation within the classical HLA class I loci.

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Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

Cited by 119 publications

References 138 publications

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1

Posttranscriptional Regulation of HLA-A Protein Expression by Alternative Polyadenylation Signals Involving the RNA-Binding Protein Syncrip

Sequence and Phylogenetic Analysis of the Untranslated Promoter Regions for HLA Class I Genes

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