Molecular Effects of Autoimmune-Risk Promoter Polymorphisms on Expression, Exon Choice, and Translational Efficiency of Interferon Regulatory Factor 5

ClarkDaniel, N; LambertJared, P; TillRodney, E; Argueta, Lissenya B.; GreenhalghKathryn, E; HenrieBrandon,; BillsTrieste,; HawkleyTyson, F; RoznikMarinya, G; SloanJason, M; MayhewVera,; WoodlandLoc,; NelsonEric, P; TsaiMeng-Hsuan,; Poole, Brian

doi:10.1089/jir.2012.0105

Cited by 7 publications

(8 citation statements)

References 55 publications

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“…The alternative alleles of rs77571059 and rs200489061 have mutation effects on up-and down-regulating IRF5 and BLK expressions, respectively (Extended Data Fig. 6) , both of which are consistent with previous in vitro experiments 46,47 .…”

Section: Main Textsupporting

confidence: 90%

Meta-analysis of 208,370 East Asians identifies 113 genomic loci and yields new non-immune cell relevant biological insights for systemic lupus erythematosus

Yin¹,

Kim²,

Suetsugu³

et al. 2020

Preprint

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Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci1-8. Nevertheless, these loci only partially explain SLE heritability and provide limited biological insight. We report the largest study of SLE in East Asians (13,377 cases and 194,993 controls), identifying 233 association signals within 113 (46 novel) genetic loci. We detect six new lead missense variants and prioritize ten most likely putative causal variants, one of which we demonstrate exhibits allele-specific regulatory effect on ACAP1 in vitro. We suggest 677 effector genes with potential for drug repurposing, and provide evidence that two distinct association signals at a single locus act on different genes (NCF2 and SMG7). We demonstrate that SLE-risk variants overlap with cell-specific active regulatory elements, notably EBNA2-mediated super-enhancers in Epstein-Barr Virus-transformed B cells, and implicate the role for non-immune cells in SLE biology. These findings shed light on genetic and biological understandings of SLE.

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Section: Main Textsupporting

confidence: 90%

Meta-analysis of 208,370 East Asians identifies 113 genomic loci and yields new non-immune cell relevant biological insights for systemic lupus erythematosus

Yin¹,

Kim²,

Suetsugu³

et al. 2020

Preprint

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“…Splice site SNP rs2004640 ( G > T on the RNA sense strand) creates an alternative ‘GT’ 5′ splice site to enable the splicing of exon 1B as an alternative first exon ( 45 ). Interestingly, IRF5 has four alternative first exons, all of which are in the 5′-UTR ( 46 ). Exon 1B is the only alternative first exon with a p53-binding site in the associated promoter region ( 47 ).…”

Section: Resultsmentioning

confidence: 99%

“…Exon 1B is the only alternative first exon with a p53-binding site in the associated promoter region ( 47 ). Furthermore, the T allele of rs2004640 has 2.7-fold higher IRF5 mRNA level ( 46 ). Overexpression of IRF5 is associated with susceptibility of autoimmune diseases, including systemic lupus erythematous, rheumatoid arthritis and multiple sclerosis ( 48 , 49 ).…”

Section: Resultsmentioning

confidence: 99%

Discover hidden splicing variations by mapping personal transcriptomes to personal genomes

Stein

Bahrami-Samani

et al. 2015

Nucleic Acids Res

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RNA-seq has become a popular technology for studying genetic variation of pre-mRNA alternative splicing. Commonly used RNA-seq aligners rely on the consensus splice site dinucleotide motifs to map reads across splice junctions. Consequently, genomic variants that create novel splice site dinucleotides may produce splice junction RNA-seq reads that cannot be mapped to the reference genome. We developed and evaluated an approach to identify ‘hidden’ splicing variations in personal transcriptomes, by mapping personal RNA-seq data to personal genomes. Computational analysis and experimental validation indicate that this approach identifies personal specific splice junctions at a low false positive rate. Applying this approach to an RNA-seq data set of 75 individuals, we identified 506 personal specific splice junctions, among which 437 were novel splice junctions not documented in current human transcript annotations. 94 splice junctions had splice site SNPs associated with GWAS signals of human traits and diseases. These involve genes whose splicing variations have been implicated in diseases (such as OAS1), as well as novel associations between alternative splicing and diseases (such as ICA1). Collectively, our work demonstrates that the personal genome approach to RNA-seq read alignment enables the discovery of a large but previously unknown catalog of splicing variations in human populations.

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“…As a member of the interferon regulatory factor family of transcription factors, IRF5 is closely associated with the inflammatory reaction and autoimmune response ( 43 , 44 ). Previous studies demonstrate inflammatory and autoimmune diseases may be associated with increased IRF5 expression levels ( 45 , 46 ).…”

Section: Discussionmentioning

confidence: 99%

Mangiferin inhibits macrophage classical activation via downregulating interferon regulatory factor 5 expression

Zhi-quan

Chen

et al. 2016

Molecular Medicine Reports

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Mangiferin is a natural polyphenol and the predominant effective component of Mangifera indica Linn. leaves. For hundreds of years, Mangifera indica Linn. leaf has been used as an ingredient in numerous traditional Chinese medicine preparations for the treatment of bronchitis. However, the pharmacological mechanism of mangiferin in the treatment of bronchitis remains to be elucidated. Macrophage classical activation is important role in the process of bronchial airway inflammation, and interferon regulatory factor 5 (IRF5) has been identified as a key regulatory factor for macrophage classical activation. The present study used the THP-1 human monocyte cell line to investigate whether mangiferin inhibits macrophage classical activation via suppressing IRF5 expression in vitro. THP-1 cells were differentiated to macrophages by phorbol 12-myristate 13-acetate. Macrophages were polarized to M1 macrophages following stimulation with lipopolysaccharide (LPS)/interferon-γ (IFN-γ). Flow cytometric analysis was conducted to detect the M1 macrophages. Reverse transcription-quantitative polymerase chain reaction was used to investigate cellular IRF5 gene expression. Levels of proinflammatory cytokines and IRF5 were assessed following cell culture and cellular homogenization using enzyme-linked immunosorbent assay. IRF5 protein and nuclei co-localization was performed in macrophages with laser scanning confocal microscope immunofluorescence analysis. The results of the present study demonstrated that mangiferin significantly inhibits LPS/IFN-γ stimulation-induced classical activation of macrophages in vitro and markedly decreases proinflammatory cytokine release. In addition, cellular IRF5 expression was markedly downregulated. These results suggest that the inhibitory effect of mangiferin on classical activation of macrophages may be exerted via downregulation of cellular IRF5 expression levels.

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Molecular Effects of Autoimmune-Risk Promoter Polymorphisms on Expression, Exon Choice, and Translational Efficiency of Interferon Regulatory Factor 5

Cited by 7 publications

References 55 publications

Meta-analysis of 208,370 East Asians identifies 113 genomic loci and yields new non-immune cell relevant biological insights for systemic lupus erythematosus

Meta-analysis of 208,370 East Asians identifies 113 genomic loci and yields new non-immune cell relevant biological insights for systemic lupus erythematosus

Discover hidden splicing variations by mapping personal transcriptomes to personal genomes

Mangiferin inhibits macrophage classical activation via downregulating interferon regulatory factor 5 expression

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