Non-coding Regions Of Genome Research Articles

Computational Prediction of Potential Vaccine Candidates From tRNA Encoded peptides (tREP) Using a Bioinformatic Workflow and Molecular Dynamics Validations.

Transfer RNAs (tRNA) are non-coding RNAs. Encouraged by biological applications discovered for peptides derived from other non-coding genomic regions, we explore the possibility of deriving epitope-based vaccines from tRNA encoded peptides (tREP) in this study. Epitope-based vaccines have been identified as an effective strategy to mitigate safety and specificity concerns observed in vaccine development. In this study, we explore the potential of tREP as a source for epitope-based vaccines for virus pathogens. We present a computational workflow that uses verified data sources and community-validated predictive tools to produce a ranked list of plausible epitope-based vaccines starting from tRNA sequences. The top epitope, bound to the predicted HLA molecule, for the virus pathogen is computationally validated through 200 ns molecular dynamics (MD) simulations followed by binding free energy calculations. The simulation results indicate that two tRNA encoded epitope-based vaccines, RRHIDIVV and IMVRFSAE for Mamastrovirus 3 and Norovirus GII, respectively, are likely candidates. Peptides originating from tRNAs provide unexplored opportunities for vaccine design. Encouraged by our previous experimental study, which established the inhibitory properties of tREPs against infectious parasites, we have proposed a computationally validated set of peptides derived from tREPs as vaccines for viral pathogens.

MUFFIN: a suite of tools for the analysis of functional sequencing data.

The large diversity of functional genomic assays allows for the characterization of non-coding and coding events at the tissue level or at a single-cell resolution. However, this diversity also leads to protocol differences, widely varying sequencing depths, substantial disparities in sample sizes, and number of features. In this work, we have built a Python package, MUFFIN, which offers a wide variety of tools suitable for a broad range of genomic assays and brings many tools that were missing from the Python ecosystem. First, MUFFIN has specialized tools for the exploration of the non-coding regions of genomes, such as a function to identify consensus peaks in peak-called assays, as well as linking genomic regions to genes and performing Gene Set Enrichment Analyses. MUFFIN also possesses a robust and flexible count table processing pipeline, comprising normalization, count transformation, dimensionality reduction, Differential Expression, and clustering. Our tools were tested on three widely different scRNA-seq, ChIP-seq and ATAC-seq datasets. MUFFIN integrates with the popular Scanpy ecosystem and is available on Conda and at https://github.com/pdelangen/Muffin.

Evolution of a Human-Specific De Novo Open Reading Frame and Its Linked Transcriptional Silencer.

In the human genome, two short open reading frames (ORFs) separated by a transcriptional silencer and a small intervening sequence stem from the gene SMIM45. The two ORFs show different translational characteristics, and they also show divergent patterns of evolutionary development. The studies presented here describe the evolution of the components of SMIM45. One ORF consists of an ultra-conserved 68 amino acid (aa) sequence, whose origins can be traced beyond the evolutionary age of divergence of the elephant shark, ~462 MYA. The silencer also has ancient origins, but it has a complex and divergent pattern of evolutionary formation, as it overlaps both at the 68 aa ORF and the intervening sequence. The other ORF consists of 107 aa. It develops during primate evolution but is found to originate de novo from an ancestral non-coding genomic region with root origins within the Afrothere clade of placental mammals, whose evolutionary age of divergence is ~99 MYA. The formation of the complete 107 aa ORF during primate evolution is outlined, whereby sequence development is found to occur through biased mutations, with disruptive random mutations that also occur but lead to a dead-end. The 107 aa ORF is of particular significance, as there is evidence to suggest it is a protein that may function in human brain development. Its evolutionary formation presents a view of a human-specific ORF and its linked silencer that were predetermined in non-primate ancestral species. The genomic position of the silencer offers interesting possibilities for the regulation of transcription of the 107 aa ORF. A hypothesis is presented with respect to possible spatiotemporal expression of the 107 aa ORF in embryonic tissues.

Whole-genome mapping of APOBEC mutagenesis in metastatic urothelial carcinoma identifies driver hotspot mutations and a novel mutational signature

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) enzymes mutate specific DNA sequences and hairpin-loop structures, challenging the distinction between passenger and driver hotspot mutations. Here, we characterized 115 whole genomes of metastatic urothelial carcinoma (mUC) to identify APOBEC mutagenic hotspot drivers. APOBEC-associated mutations were detected in 92% of mUCs and were equally distributed across the genome, while APOBEC hotspot mutations (ApoHMs) were enriched in open chromatin. Hairpin loops were frequent targets of didymi (twins in Greek), two hotspot mutations characterized by the APOBEC SBS2 signature, in conjunction with an uncharacterized mutational context (Ap[C>T]). Next, we developed a statistical framework that identified ApoHMs as drivers in coding and non-coding genomic regions of mUCs. Our results and statistical framework were validated in independent cohorts of 23 non-metastatic UCs and 3,744 samples of 17 metastatic cancers, identifying cancer-type-specific drivers. Our study highlights the role of APOBEC in cancer development and may contribute to developing novel targeted therapy options for APOBEC-driven cancers.

Abstract 7358: Role of noncoding genome architecture in esophageal cancer

Abstract Esophageal Cancer is a deadly disease with a tendency to be diagnosed at the later stages. Considered a rare disease, accounting for 1.1% of all cancers, EC comprises 2.6% of all cancer deaths. The survival rate for all stages is 21.7%. However, the survival rate decreases to 5.6 % for advanced-stage cancers. EC is more common in men and associated with older age and heavy alcohol and tobacco use. In the last 25 years, the death rate of EC has been decreasing slightly from 4.3 to 3.7. The death rates for lung, prostate, and colon cancers have decreased by half in the same time frame. Therefore, novel therapies and biomarkers are urgently needed to accelerate survival and reduce the death rates by at least half for patients with EC.We previously completed exome sequencing in a small sample size and observed that the mutations in the noncoding regions of the EC genome are highly affected. In this study, we perform exome sequencing in 110 paired esophageal tumors and normal tissues using an Agilent SSELXT HS Exon V8+UTR library enrichment kit. Twelve paired EC and normal tissues are sequenced using the PacBio Hifi system.In WES, we detected almost half of the noncoding region mutations in the 3UTR and 2kb downstream regions of the genome, significantly affecting 51 oncogenic or tumor suppressor genes. In addition, the involved genes are over-represented in critical signaling pathways and transcriptional regulation of pluripotent stem cells. The number of changes in the 5UTR and 2kb upstream are similar to the number of variations in the intronic regions. Apoptosis, stress response, and DNA double-strand break repair pathways are affected by 5UTR mutations. Mutations in the intronic regions frequently occurred in pro-tumorigenic immune regulation genes, such as IL-33 and IL-6, and oncogene-induced senescence.The combined effect of these genetic and coding region mutations on oncogenes, significant signaling pathways, cancer cell stemness, DNA damage repair pathways, and immune system regulation may significantly impact poor prognosis in EC patients. Further studies will verify the effectiveness of targeting these genes for developing candidate therapeutics. Citation Format: Hayriye Verda Erkizan, Robert Wadleigh. Role of noncoding genome architecture in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7358.

Origin of functional de novo genes in humans from "hopeful monsters".

For a long time, it was believed that new genes arise only from modifications of preexisting genes, but the discovery of de novo protein-coding genes that originated from noncoding DNA regions demonstrates the existence of a "motherless" origination process for new genes. However, the features, distributions, expression profiles, and origin modes of these genes in humans seem to support the notion that their origin is not a purely "motherless" process; rather, these genes arise preferentially from genomic regions encoding preexisting precursors with gene-like features. In such a case, the gene loci are typically not brand new. In this short review, we will summarize the definition and features of human de novo genes and clarify their process of origination from ancestral non-coding genomic regions. In addition, we define the favored precursors, or "hopeful monsters," for the origin of de novo genes and present a discussion of the functional significance of these young genes in brain development and tumorigenesis in humans. This article is categorized under: RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution.

Conceptual breakthroughs of the long noncoding RNA functional system and its endogenous regulatory role in the cancerous regime.

Long noncoding RNAs (lncRNAs) derived from noncoding regions in the human genome were once regarded as junks with no biological significance, but recent studies have shown that these molecules are highly functional, prompting an explosion of studies on their biology. However, these recent efforts have only begun to recognize the biological significance of a small fraction (< 1%) of the lncRNAs. The basic concept of these lncRNA functions remains controversial. This controversy arises primarily from conventional biased observations based on limited datasets. Fortunately, emerging big data provides a promising path to circumvent conventional bias to understand an unbiased big picture of lncRNA biology and advance the fundamental principles of lncRNA biology. This review focuses on big data studies that break through the critical concepts of the lncRNA functional system and its endogenous regulatory roles in all cancers. lncRNAs have unique functional systems distinct from proteins, such as transcriptional initiation and regulation, and they abundantly interact with mitochondria and consume less energy. lncRNAs, rather than proteins as traditionally thought, function as the most critical endogenous regulators of all cancers. lncRNAs regulate the cancer regulatory regime by governing the endogenous regulatory network of all cancers. This is accomplished by dominating the regulatory network module and serving as a key hub and top inducer. These critical conceptual breakthroughs lay a blueprint for a comprehensive functional picture of the human genome. They also lay a blueprint for combating human diseases that are regulated by lncRNAs.

Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control?

Genomic instability, a hallmark of cancer, is a direct consequence of the inactivation of the tumor suppressor protein p53. Genetically modified mouse models and human tumor samples have revealed that p53 loss results in extensive chromosomal abnormalities, from copy number alterations to structural rearrangements. In this perspective article we explore the multifaceted relationship between p53, genomic stability, and epigenetic control, highlighting its significance in cancer biology. p53 emerges as a critical regulator of DNA repair mechanisms, influencing key components of repair pathways and directly participating in DNA repair processes. p53 role in genomic integrity however extends beyond its canonical functions. p53 influences also epigenetic landscape, where it modulates DNA methylation and histone modifications. This epigenetic control impacts the expression of genes involved in tumor suppression and oncogenesis. Notably, p53 ability to ensure cellular response to DNA demethylation contributes to the maintenance of genomic stability by preventing unscheduled transcription of repetitive non-coding genomic regions. This latter indicates a causative relationship between the control of epigenetic stability and the maintenance of genomic integrity in p53-mediated tumor suppression. Understanding these mechanisms offers promising avenues for innovative therapeutic strategies targeting epigenetic dysregulation in cancer and emphasizes the need for further research to unravel the complexities of this relationship. Ultimately, these insights hold the potential to transform cancer treatment and prevention strategies.

Identification of conserved skeletal enhancers associated with craniosynostosis risk genes.

Craniosynostosis, defined by premature fusion of one or multiple cranial sutures, is a common congenital defect affecting more than 1/2000 infants and results in restricted brain expansion. Single gene mutations account for 15%-20% of cases, largely as part of a syndrome, but the majority are nonsyndromic with complex underlying genetics. We hypothesized that the two noncoding genomic regions identified by a GWAS for craniosynostosis contain distal regulatory elements for the risk genes BMPER and BMP2. To identify such regulatory elements, we surveyed conserved noncoding sequences from both risk loci for enhancer activity in transgenic Danio rerio. We identified enhancers from both regions that direct expression to skeletal tissues, consistent with the endogenous expression of bmper and bmp2. For each locus, we also found a skeletal enhancer that also contains a sequence variant associated with craniosynostosis risk. We examined the activity of each enhancer during craniofacial development and found that the BMPER-associated enhancer is active in the restricted region of cartilage closely associated with frontal bone initiation. The same enhancer is active in mouse skeletal tissues, demonstrating evolutionarily conserved activity. Using enhanced yeast one-hybrid assays, we identified transcription factors that bind each enhancer and observed differential binding between alleles, implicating multiple signaling pathways. Our findings help unveil the genetic mechanism of the two craniosynostosis risk loci. More broadly, our combined in vivo approach is applicable to many complex genetic diseases to build a link between association studies and specific genetic mechanisms.

Functional SNPs in SYISL promoter significantly affect muscle fiber density and muscle traits in pigs.

Our previous studies showed that SYISL is a negative regulator of muscle growth and regeneration in mice, pigs and humans. SYISL knockout resulted in an increase in the density of muscle fibers and muscle growth. However, it is unclear whether there are natural mutations in pig SYNPO2 intron sense-overlapping lncRNA (pSYISL) that affect the expression of pSYISL and muscle growth traits. In this study, three SNPs in exons and six SNPs within the promoter of pSYISL were identified. Association analysis showed that the two SNPs in exons are significantly associated with loin muscle area (p < 0.05); the six SNPs in the promoter that show complete linkage are significantly associated with live backfat thickness and live loin muscle area in American Large White pigs. Bioinformatics and luciferase reporter assays as well as in vitro binding experiments indicated that the mutation of SNP rs702045770 (g.539G>A) leads to the loss of YY1 binding to the promoter, thus affecting the expression level of pSYISL, and we found that Jiangshan Black pigs with genotype GG have a higher expression level of pSYISL than genotype AA individuals, but the muscle fiber density was significantly lower than in genotype AA individuals. Furthermore, the association analysis showed that the carcass backfat thickness of genotype GG of SNP rs702045770 was significantly higher than that of other genotypes in (Pietrain × Duroc) × (Landrace × Yorkshire) crossbred pigs (p < 0.05). The glycolytic potential of genotype GG was significantly higher than that of other genotypes (p < 0.05). These results provide novel insight into the identification of functional SNPs in non-coding genomic regions.

Regulome-wide association study identifies genetically driven accessible regions associated with pancreatic cancer risk.

Genome-wide association studies (GWAS) have identified two dozen genetic variants that are associated with the risk of pancreatic ductal adenocarcinoma (PDAC), a deadly malignancy. However, a majority of these variants are located in noncoding regions of the genome, which limits the translation of GWAS findings into clinical applications. The regulome-wide association study (RWAS) is a recently developed method for identifying TF binding-induced accessibility regions for diseases. However, their potential connection to PDAC has yet to be fully explored. We evaluated the associations between genetically predicted levels of chromatin accessibility and risk of PDAC by using pan-cancer chromatin accessibility genetic prediction models. Our analysis included 8275 cases and 6723 controls from the PanScan (I, II, and III) and PanC4 consortia. To further refine our results, we also integrated genes associated to allele-specific accessibility quantitative trait loci (as-aQTL) and TF motifs located in the as-aQTL. We found that 50 chromatin accessibility features were associated with PDAC risk at a false discovery rate (FDR) of less than 0.05. A total of 28 RWAS peaks were identified as conditionally significant. By integrating the results from as-aQTL, motif analysis, and RWAS, we identified candidate causal regulatory elements for two potential chromatin accessibility regions (THCA_89956 and ESCA_89167) that are associated with PDAC risk. Our study identified chromatin accessibility features in noncoding genomic regions that are associated with PDAC risk. We also predicted the associated genes and disrupt motifs. Our findings provide new insights into the regulatory mechanisms of noncoding regions for pancreatic tumorigenesis.

Protein-coding potential of non-canonical open reading frames in human transcriptome

In recent years, proteogenomics and ribosome profiling studies have identified a large number of proteins encoded by noncoding regions in the human genome. They are encoded by small open reading frames (sORFs) in the untranslated regions (UTRs) of mRNAs and long non-coding RNAs (lncRNAs). These sORF encoded proteins (SEPs) are often <150AA and show poor evolutionary conservation. A subset of them have been functionally characterized and shown to play an important role in fundamental biological processes including cardiac and muscle function, DNA repair, embryonic development and various human diseases. How many novel protein-coding regions exist in the human genome and what fraction of them are functionally important remains a mystery. In this review, we discuss current progress in unraveling SEPs, approaches used for their identification, their limitations and reliability of these identifications. We also discuss functionally characterized SEPs and their involvement in various biological processes and diseases. Lastly, we provide insights into their distinctive features compared to canonical proteins and challenges associated with annotating these in protein reference databases.

Diagnostic genome sequencing improves diagnostic yield: a prospective single-centre study in 1000 patients with inherited eye diseases

PurposeGenome sequencing (GS) is expected to reduce the diagnostic gap in rare disease genetics. We aimed to evaluate a scalable framework for genome-based analyses ‘beyond the exome’ in regular care...

Abstract 135: The Noncoding Haplotype Region Of Blood Pressure-associated Single Nucleotide Polymorphism Rs1173771 Regulates The Expression Of Natriuretic Peptide Receptor C

Genome-wide association studies have identified 1,071 loci containing 26,585 single nucleotide polymorphisms (SNPs) as associated with blood pressure (BP). These loci together explain more than 25% of BP heritability. The BP-associated SNP rs1173771 has been associated with NPR3 expression in human tissues. NPR3 encodes natriuretic peptide receptor C (NPR-C). The haplotype in linkage disequilibrium (LD) with rs1173771 contains 11 SNPs spanning a noncoding genomic region of more than 17 kbp. The haplotype region is located 126 kbp from the transcription start site of NPR3 . We used genome editing to examine the effect of the noncoding haplotype region in LD with rs1173771 on gene expression. We employed a CRISPR/Cas9 mediated genetic engineering approach to delete the 17 kbp haplotype region in a human induced pluripotent stem cell (iPSC) line. Two clones of iPSCs with homozygous deletion of the 17 kbp region were obtained after screening 50 single cell clones. The genomic modification was confirmed by PCR, Sanger sequencing, and whole genome sequencing. Immunofluorescence staining for pluripotency markers indicated that pluripotency was retained following the genome editing procedures. Each edited iPSC clone and the unedited iPSC line were differentiated into endothelial cells (iECs) in 3 independent rounds of differentiation. Real-time PCR analysis showed a 1.59±0.17-fold upregulation of NPR3 mRNA in iECs with the haplotype region deletion compared to unedited iECs (n=11 and 7, p&lt;0.05). The expression of other neighboring genes ( SUB1 and TARS ) and a distal gene ( MRPS30 ) was not significantly affected by the deletion. The results provide definitive evidence that the noncoding haplotype region in LD with BP-associated SNP rs1173771 regulates the expression of natriuretic peptide receptor C in iECs.

BamQuery: a proteogenomic tool to explore the immunopeptidome and prioritize actionable tumor antigens

MHC-I-associated peptides deriving from non-coding genomic regions and mutations can generate tumor-specific antigens, including neoantigens. Quantifying tumor-specific antigens’ RNA expression in malignant and benign tissues is critical for discriminating actionable targets. We present BamQuery, a tool attributing an exhaustive RNA expression to MHC-I-associated peptides of any origin from bulk and single-cell RNA-sequencing data. We show that many cryptic and mutated tumor-specific antigens can derive from multiple discrete genomic regions, abundantly expressed in normal tissues. BamQuery can also be used to predict MHC-I-associated peptides immunogenicity and identify actionable tumor-specific antigens de novo.

Whole-genome resequencing of common bean elite breeding lines

The expansion of bean genome technologies has prompted new perspectives on generating resources and knowledge essential to research and implementing biotechnological tools for the practical operations of plant breeding programs. This study aimed to resequence the entire genome (whole genome sequencing—WGS) of 40 bean genotypes selected based on their significance in breeding programs worldwide, with the objective of generating an extensive database for the identification of single nucleotide polymorphisms (SNPs). Over 6 million SNPs were identified, distributed across the 11 bean chromosomes. After quality variant filtering, 420,509 high-quality SNPs were established, with an average of 38,228 SNPs per chromosome. These variants were categorized based on their predicted effects, revealing that the majority exerted a modifier impact on non-coding genome regions (94.68%). Notably, a significant proportion of SNPs occurred in intergenic regions (62.89%) and at least one SNP was identified in 58.63% of the genes annotated in the bean genome. Of particular interest, 7841 SNPs were identified in 85% of the putative plant disease defense-related genes, presenting a valuable resource for crop breeding efforts. These findings provide a foundation for the development of innovative and broadly applicable technologies for the routine selection of superior genotypes in global bean improvement and germplasm characterization programs.

Integrated multiomics analysis of chromosome 19 miRNA cluster in bladder cancer

With 46 microRNAs (miRNAs) embedded tandemly over a distance of ~100 kb, chromosome 19 microRNA cluster (C19MC) is the largest miRNA cluster in the human genome. The C19MC is transcribed from a long noncoding genomic region and is usually expressed simultaneously at a higher level. Hence, we performed an integrative multiomics data analysis to examine C19MC regulation, expression patterns, and their impact on bladder cancer (BCa). We found that 43 members of C19MC were highly expressed in BCa. However, its co-localization with recurrent copy number variation (CNV) gain was not statistically significant to implicate its upregulation. It has been reported that C19MC expression is regulated by a well-established CpG island situated 17.6 kb upstream of the transcription start site, but we found that CpG probes at this island were hypomethylated, which was not statistically significant in the BCa cohort. In addition, the promoter region of C19MC is strongly regulated by a group of seven transcription factors (NR2F6, SREBF1, TBP, GATA3, GABPB1, ETV4, and ZNF444) and five chromatin modifiers (SMC3, KDMA1, EZH2, RAD21, and CHD7). Interestingly, these 12 genes were found to be overexpressed in BCa patients. Further, C19MC targeted 42 tumor suppressor (TS) genes that were downregulated, of which 15 were significantly correlated with patient survival. Our findings suggest that transcription factors and chromatin modifiers at the promoter region may regulate C19MC overexpression. The upregulated C19MC members, transcription regulators, and TS genes can be further exploited as potential diagnostic and prognostic indicators as well as for therapeutic management of BCa.

CVD-associated SNPs with regulatory potential reveal novel non-coding disease genes

BackgroundCardiovascular diseases (CVDs) are the leading cause of death worldwide. Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) appearing in non-coding genomic regions in CVDs. The SNPs may alter gene expression by modifying transcription factor (TF) binding sites and lead to functional consequences in cardiovascular traits or diseases. To understand the underlying molecular mechanisms, it is crucial to identify which variations are involved and how they affect TF binding.MethodsThe SNEEP (SNP exploration and analysis using epigenomics data) pipeline was used to identify regulatory SNPs, which alter the binding behavior of TFs and link GWAS SNPs to their potential target genes for six CVDs. The human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs), monoculture cardiac organoids (MCOs) and self-organized cardiac organoids (SCOs) were used in the study. Gene expression, cardiomyocyte size and cardiac contractility were assessed.ResultsBy using our integrative computational pipeline, we identified 1905 regulatory SNPs in CVD GWAS data. These were associated with hundreds of genes, half of them non-coding RNAs (ncRNAs), suggesting novel CVD genes. We experimentally tested 40 CVD-associated non-coding RNAs, among them RP11-98F14.11, RPL23AP92, IGBP1P1, and CTD-2383I20.1, which were upregulated in hiPSC-CMs, MCOs and SCOs under hypoxic conditions. Further experiments showed that IGBP1P1 depletion rescued expression of hypertrophic marker genes, reduced hypoxia-induced cardiomyocyte size and improved hypoxia-reduced cardiac contractility in hiPSC-CMs and MCOs.ConclusionsIGBP1P1 is a novel ncRNA with key regulatory functions in modulating cardiomyocyte size and cardiac function in our disease models. Our data suggest ncRNA IGBP1P1 as a potential therapeutic target to improve cardiac function in CVDs.

Shining a light on the dark proteome: Non-canonical open reading frames and their encoded miniproteins as a new frontier in cancer biology.

In the decades following the discovery that genes encode proteins, scientists have tried to exhaustively and comprehensively characterize the human genome. Recent advances in computational methods along with transcriptomic and proteomic techniques have now shown that historically non-coding genomic regions may contain non-canonical open reading frames (ncORFs), which may encode functional miniproteins or otherwise exert regulatory activity through coding-independent functions. Increasingly, it is clear that these ncORFs may play critical roles in major human diseases such as cancer. In this review, we summarize the history and current progress of ncORF research and explore the known functions of ncORFs and the miniproteins they may encode. We particularly highlight the emerging body of evidence supporting a role for ncORFs and miniproteins contributions in cancer. Finally, we provide a blueprint for high-priority areas of future research for ncORFs in cancer, focusing on ncORF detection, functional characterization, and therapeutic intervention.

LncRNA ARGI Contributes to Virus-Induced Pancreatic β Cell Inflammation Through Transcriptional Activation of IFN-Stimulated Genes.

Type 1 diabetes (T1D) is a complex autoimmune disease that develops in genetically susceptible individuals. Most T1D-associated single nucleotide polymorphisms (SNPs) are located in non-coding regions of the human genome. Interestingly, SNPs in long non-coding RNAs (lncRNAs) may result in the disruption of their secondary structure, affecting their function, and in turn, the expression of potentially pathogenic pathways. In the present work, the function of a virus-induced T1D-associated lncRNA named ARGI (Antiviral Response Gene Inducer) is characterized. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic β cells and binds to CTCF to interact with the promoter and enhancer regions of IFNβ and interferon-stimulated genes, promoting their transcriptional activation in an allele-specific manner. The presence of the T1D risk allele in ARGI induces a change in its secondary structure. Interestingly, the T1D risk genotype induces hyperactivation of type I IFN response in pancreatic β cells, an expression signature that is present in the pancreas of T1D patients. These data shed light on the molecular mechanisms by which T1D-related SNPs in lncRNAs influence pathogenesis at the pancreatic β cell level and opens the door for the development of therapeutic strategies based on lncRNA modulation to delay or avoid pancreatic β cell inflammation in T1D.