Cis-regulation of IRF5expression is unable to fully account for systemic lupus erythematosus association: analysis of multiple experiments with lymphoblastoid cell lines

Alonso-Pérez, Elisa; Suarez-Gestal, Marian; Calaza, Manuel; Kwan, Tony; Majewski, Jacek; Gómez-Reino, Juan J.; González, Antonio G.

doi:10.1186/ar3343

Cited by 13 publications

(17 citation statements)

References 36 publications

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“…Cis -acting variants have been identified in the IRF5 gene that associate with elevated expression, but the data on cis regulation of IRF5 alternative splicing is unclear [7]–[8], [55]. Indeed, recent findings by Alonso-Perez et al indicate that cis -regulation of IRF5 expression is not enough to fully account for IRF5 association with SLE susceptibility, suggesting that other mechanisms exist that regulate functional changes in IRF5 [56]. These data are confirmatory of earlier work in the lab revealing that genotype alone was not enough to account for elevated IRF5 expression in primary immune cells of SLE patients and enhanced IRF5 alternative splicing was, at least in part, due to elevated levels of spliceosome components in SLE patients as overexpression of many of these factors led to increased IRF5 alternative splicing [15].…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq for Enrichment and Analysis of IRF5 Transcript Expression in SLE

Stone

Du²,

Feng

et al. 2013

PLoS ONE

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Polymorphisms in the interferon regulatory factor 5 (IRF5) gene have been consistently replicated and shown to confer risk for or protection from the development of systemic lupus erythematosus (SLE). IRF5 expression is significantly upregulated in SLE patients and upregulation associates with IRF5-SLE risk haplotypes. IRF5 alternative splicing has also been shown to be elevated in SLE patients. Given that human IRF5 exists as multiple alternatively spliced transcripts with distinct function(s), it is important to determine whether the IRF5 transcript profile expressed in healthy donor immune cells is different from that expressed in SLE patients. Moreover, it is not currently known whether an IRF5-SLE risk haplotype defines the profile of IRF5 transcripts expressed. Using standard molecular cloning techniques, we identified and isolated 14 new differentially spliced IRF5 transcript variants from purified monocytes of healthy donors and SLE patients to generate an IRF5 variant transcriptome. Next-generation sequencing was then used to perform in-depth and quantitative analysis of full-length IRF5 transcript expression in primary immune cells of SLE patients and healthy donors by next-generation sequencing. Evidence for additional alternatively spliced transcripts was obtained from de novo junction discovery. Data from these studies support the overall complexity of IRF5 alternative splicing in SLE. Results from next-generation sequencing correlated with cloning and gave similar abundance rankings in SLE patients thus supporting the use of this new technology for in-depth single gene transcript profiling. Results from this study provide the first proof that 1) SLE patients express an IRF5 transcript signature that is distinct from healthy donors, 2) an IRF5-SLE risk haplotype defines the top four most abundant IRF5 transcripts expressed in SLE patients, and 3) an IRF5 transcript signature enables clustering of SLE patients with the H2 risk haplotype.

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Section: Discussionmentioning

confidence: 99%

RNA-Seq for Enrichment and Analysis of IRF5 Transcript Expression in SLE

Stone

Du²,

Feng

et al. 2013

PLoS ONE

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“…Studies of Alonso-Perez et al . [ 34 ] and Lofgren et al . [ 35 ] demonstrated mutant allele A induces up-regulation of IRF5 mRNA and IRF5 protein in SLE patients.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association study combined with biological context can reveal more disease-related SNPs altering microRNA target seed sites

Yang

Zhang

et al. 2014

BMC Genomics

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BackgroundEmerging studies demonstrate that single nucleotide polymorphisms (SNPs) resided in the microRNA recognition element seed sites (MRESSs) in 3′UTR of mRNAs are putative biomarkers for human diseases and cancers. However, exhaustively experimental validation for the causality of MRESS SNPs is impractical. Therefore bioinformatics have been introduced to predict causal MRESS SNPs. Genome-wide association study (GWAS) provides a way to detect susceptibility of millions of SNPs simultaneously by taking linkage disequilibrium (LD) into account, but the multiple-testing corrections implemented to suppress false positive rate always sacrificed the sensitivity. In our study, we proposed a method to identify candidate causal MRESS SNPs from 12 GWAS datasets without performing multiple-testing corrections. Alternatively, we used biological context to ensure credibility of the selected SNPs.ResultsIn 11 out of the 12 GWAS datasets, MRESS SNPs were over-represented in SNPs with p-value ≤ 0.05 (odds ratio (OR) ranged from 1.1 to 2.4). Moreover, host genes of susceptible MRESS SNPs in each of the 11 GWAS dataset shared biological context with reported causal genes. There were 286 MRESS SNPs identified by our method, while only 13 SNPs were identified by multiple-testing corrections with a given threshold of 1 × 10−5, which is a common cutoff used in GWAS. 27 out of the 286 candidate SNPs have been reported to be deleterious while only 2 out of 13 multiple-testing corrected SNPs were documented in PubMed. MicroRNA-mRNA interactions affected by the 286 candidate SNPs were likely to present negatively correlated expression. These SNPs introduced greater alternation of binding free energy than other MRESS SNPs, especially when grouping by haplotypes (4210 vs. 4105 cal/mol by mean, 9781 vs. 8521 cal/mol by mean, respectively).ConclusionsMRESS SNPs are promising disease biomarkers in multiple GWAS datasets. The method of integrating GWAS p-value and biological context is stable and effective for selecting candidate causal MRESS SNPs, it reduces the loss of sensitivity compared to multiple-testing corrections. The 286 candidate causal MRESS SNPs provide researchers a credible source to initialize their design of experimental validations in the future.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-669) contains supplementary material, which is available to authorized users.

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“…Each non-coding exon corresponds to a different promoter ( 26 ), allowing alternative splicing of the gene. There are over 100 known polymorphisms of IRF5, but only four are thought to be functional ( 27 ). Three of these polymorphisms are located in non-coding regions of IRF5.…”

Section: Introductionmentioning

confidence: 99%

Lineage-Specific Functionality of an Interferon Regulatory Factor 5 Lupus Risk Haplotype: Lack of B Cell Intrinsic Effects

et al. 2018

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Interferon regulatory factor 5 (IRF5) is widely recognized as a risk locus for systemic lupus erythematosus (SLE). Risk gene and IRF5 activation is triggered through toll-like receptor signaling. In myeloid cells, this leads to production of type I interferon and inflammatory cytokines, with enhanced production in cells of individuals harboring IRF5 risk alleles. Mouse models have also demonstrated the importance of IRF5 in B cell function, particularly plasma cell differentiation and isotype switching. Here, we evaluated the major SLE risk haplotype of IRF5 on the functional attributes of freshly isolated B cells from human subjects who do not have evidence of SLE or other forms of autoimmunity. We took this approach to avoid the complications of studying genotype-phenotype relationships in B cells that have been chronically exposed to an inflammatory disease environment before isolation. We focused on B cell endophenotypes that included gene expression, antibody secretion, class switching, and apoptotic susceptibility. We performed IRF5 overexpression studies, genetic reporter assays and electro-mobility shift assays on B and myeloid cell lines. Somewhat surprisingly, the results of our analyses indicate that IRF5 risk genotypes do not have a B cell intrinsic effect on these B cell functions. By contrast, we confirmed that the IRF5 risk and non-risk haplotypes exert differential effects in myeloid cells, including an increased susceptibility to apoptosis conferred by the risk haplotype. We also demonstrated an increased binding of the transcription factor specificity protein 1 to an insertion/deletion present in the risk haplotype. Our findings raise the specter that genetic risk alleles can have complex and unexpected lineage-specific effects, and these must be carefully considered when guiding or developing therapies based on understanding disease risk haplotypes.

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Cis-regulation of IRF5expression is unable to fully account for systemic lupus erythematosus association: analysis of multiple experiments with lymphoblastoid cell lines

Cited by 13 publications

References 36 publications

RNA-Seq for Enrichment and Analysis of IRF5 Transcript Expression in SLE

RNA-Seq for Enrichment and Analysis of IRF5 Transcript Expression in SLE

Genome-wide association study combined with biological context can reveal more disease-related SNPs altering microRNA target seed sites

Lineage-Specific Functionality of an Interferon Regulatory Factor 5 Lupus Risk Haplotype: Lack of B Cell Intrinsic Effects

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