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View / Download Thynn HN, Chen XF, Dong SS, Guo Y, Yang TL. Commentary: An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long-Range Chromatin Loop Formation. J Immunological Sci. (2020); 4(1): 6-9 Journal of Immunological Sciences Commentary Article Open Access Commentary: An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long- Range Chromatin Loop Formation Hlaing Nwe Thynn, Xiao-Feng Chen, Shan-Shan Dong, Yan Guo, Tie-Lin Yang* Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technol- ogy, Xi’an Jiaotong University, Xi’an, Shaanxi 710049, P. R. China Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis Article Info Article Notes sharing similar pathogenic features. Genetic factors play important Received: February 14, 2020 (SSc) are two typical inflammatory systemic1 autoimmune diseases Accepted: March 20, 2020 roles in the pathogenesis of both diseases . We have witnessed huge success of genome-wide association studies (GWASs) in identifying *Correspondence: hundreds of susceptibility genetic variants associated with SLE Dr. Tie-Lin Yang, Ph.D., Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical and SSc, however, over 90% of which are located in noncoding Informatics & Genomics Center, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi into biological insights towards clinical applications. Currently, 710049, P. R. China; Telephone No: 86-29-82668463; Email: regions. It is challenging and important to translate GWAS findings [email protected]. compared with traditional genetic association studies, functional studies characterizing causal functional variants and downstream © 2020 Yang TL. This article is distributed under the terms of molecular mechanisms at disease susceptibility loci are still orders the Creative Commons Attribution 4.0 International License. of magnitude fewer. With the emergence of multiple omics technologies including genomics, epigenomics, transcriptomics, proteomics and metabolomics, the deposits of omics databases strongly speed up complex diseases2. Our recent review3 highlighted the advantages andthe clarificationchallenges ofof multiplemolecular omics mechanisms data. The associated methodologies with human using single-omics data explain limited insights into the biological mechanisms of a disease. The advanced methodologies incorporating with multi-omics approaches followed by functional experiments comprehensively capture more biological insights, which result in better understanding of molecular mechanisms and pathogenesis of diseases3. Therefore, integrated multi-omics approaches become powerful tools for interpretation of GWAS susceptibility loci into clinical application. In our publication4, we provided a mechanistic insight that a noncoding GWAS variant associated with both SLE and the distal gene IRF5 expression mediated by transcription factor EVI1SSc acted through as an the allele-specific current robust strong strategies, enhancer including to directly integrated regulate multi-omics approaches and follow-up functional experiments. The IRF5-TNPO3 locus at 7q32.1 possesses one of the strongest association signals with both SLE and SSc5,6, in which IRF5 (interferon regulatory factor 5) is a well-known immunologic gene7, whereas the immunologically functional role of TNPO3 (transportin 3) is still unknown. It is interestingly motivated to investigate the regulatory mechanisms underlying TNPO3. Recent emerging studies at many GWAS loci have demonstrated that noncoding variants within potential regulatory elements regulate their distal target Page 6 of 9 Thynn HN, Chen XF, Dong SS, Guo Y, Yang TL. Commentary: An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Journal of Immunological Sciences Long-Range Chromatin Loop Formation. J Immunological Sci. (2020); 4(1): 6-9 genes associated with diseases via chromatin looping of improving the substantial databases, eQTL analysis interactions8-11. Our study indicated that the nearest gene represents one of the most straightforward approaches to of disease-associated SNPs or the gene harboring disease- associated SNPs may not be the true target genes in many loci in relevant cell/tissue types, which provides evidence the identification of candidate susceptibility genes16. atIn riskour study, cis-eQTL analysis using various datasets consistently GWAS loci. This investigation might fulfill the gap between demonstratedof allele-specific that functional IRF5 instead impacts of the for nearby risk SNPs gene TNPO3 Prioritizing variants within GWAS-associated regions GWAS findings and clinical application of diseases. was the distal target gene (~118 kb) of rs13239597. In this case, we implemented high-throughput chromatin insights into the conversion of statistical associations into interaction (Hi-C) analysis, topologically associating targetis the genesfirst crucialand disease step biology.of current As theresearch numbers to ofprovide GWAS domain (TAD) analysis and chromosome conformation samples become enormous, the association signals at GWAS capture (3C) assay to corroborate the long-range chromatin loci are also increasing. Stepwise conditional analysis is interaction between rs13239597 and its distal target gene a comprehensive strategy to identify additional multiple IRF5. Hi-C analysis is a unique and powerful tool to reveal 12. the ultimate connectivity between the genomic sequence associationannotation is signals also a potentialat a previously strategy identified to select GWAS and prioritize locus between distant genomic elements such as genes and candidateBayesian fine-mapping causal variants followed within GWAS-associated by functional epigenomics regions13. regulatoryand spatial elementsconformation,17. Besides, and specific TAD islong-range a self-interacting contacts Several previous studies applying stepwise conditional genomic region, which means that DNA sequences within a TAD boundary physically interact with each other more additional molecular mechanisms underlying GWAS loci. frequently than with sequences outside the TAD18. In our Foranalysis example, and BayesianGalarneau fine-mapping successfully detected study, Hi-C and TAD analyses were performed using the SNPs at BCL11A, HBS1L-MYB 19 et al. identified seven independent robust databases, including Capture Hi-C data , Hi-C data from 4D Genome databases20,21, ChIA-PET data from UCSC could explain heritable variation andin hemoglobin β-globin levelsloci, using from ENCODE databases22 and TAD data from GEO databases23. 38.6%stepwise to conditional49.5%14 analysis and fine-mapping, which Moreover, 3C assay was performed as a follow-up functional mapping at immune-related loci, 48 new multiple sclerosis . With high-resolution Bayesian fine- experiment, which is a pioneer technique to investigate the three-dimensional structure of chromatin and to analyze catalogue of multiple sclerosis risk variants15. In our study, susceptibility variants were identified, which enhanced the long-range looping interactions between any pair of selected genomic loci24. When integrating multi-omics data independently associated SLE risk variants in either IRF5 and employing follow-up functional assay, the long-range weor TNPO3 first uncovered region. We that could 7q32.1 further locus prioritize encompassed a potentially several chromatin looping interaction between rs13239597 and functional independent variant rs13239597 located in its distal target gene IRF5 could be convincingly validated. TNPO3 promoter region through the strategies combining Furthermore, another follow-up functional experiments mapping and functional epigenomics annotation. It was alsostepwise found conditionalthat the SNP analysis,rs13239597 Bayesian resided genomic within or fine-near regulation between rs13239597 and IRF5. We performed putative regulatory enhancer elements in three immune- dual-luciferasewere also performed reporter assayto validate that is a widelythe allele-specific used tool to related cell lines. Here, the comprehensive strategies study gene expression at transcription level, and CRISPR- incorporating with genomics and epigenomics data Cas9 that is currently the simplest, most versatile and predicted a newly functional GWAS variant associated with precise method of genetic manipulation to edit parts of the both SLE and SSc, illuminating the potential application genome. We also validated whether the detected regulatory of our strategies for more GWAS loci. This approach could activity of rs13239597 on the distal gene IRF5 be used to investigate more functional causal variants due to the intermediary effect of the nearby gene TNPO3 associated with other complex diseases. by gene-silencing. Taken together, these experimentalwas fictitious results prominently revealed that rs13239597 acted as The disease-associated SNPs located in noncoding expression regions of the human genome do not have their protein IRF5 independently of TNPO3. To further vigorously reinforce an allele-specific enhancer regulating , we expression of their target genes associated with disease IRF5 encourage to use the base-editing techniques and genome- phenotypesfunctions to16 influence, however, they could affect the editedthe allele-specific mouse models functionality that were of not
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