Dysregulated long non-coding RNA in Sjögren's disease impacts both interferon and adaptive immune responses.

Objective: Sjögren's disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjD) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised.

Variants on the UBE2L3/YDJC Autoimmune Disease Risk Haplotype Increase UBE2L3 Expression by Modulating CCCTC-Binding Factor and YY1 Binding.

Objective: Genetic variants spanning UBE2L3 are associated with increased expression of the UBE2L3-encoded E2 ubiquitin-conjugating enzyme H7 (UbcH7), which facilitates activation of proinflammatory NF-κB signaling and susceptibility to autoimmune diseases. We undertook this study to delineate how genetic variants carried on the UBE2L3/YDJC autoimmune risk haplotype function to drive hypermorphic UBE2L3 expression.

Methods: We used bioinformatic analyses, electrophoretic mobility shift assays, and luciferase reporter assays to identify and functionally characterize allele-specific effects of risk variants positioned in chromatin accessible regions of immune cells.

Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks.

Genetic variants can confer risk to complex genetic diseases by modulating gene expression through changes to the epigenome. To assess the degree to which genetic variants influence epigenome activity, we integrate epigenetic and genotypic data from lupus patient lymphoblastoid cell lines to identify variants that induce allelic imbalance in the magnitude of histone post-translational modifications, referred to herein as histone quantitative trait loci (hQTLs). We demonstrate that enhancer hQTLs are enriched on autoimmune disease risk haplotypes and disproportionately influence gene expression variability compared with non-hQTL variants in strong linkage disequilibrium.

Single-cell analysis of glandular T cell receptors in Sjögren's syndrome.

CD4 T cells predominate in salivary gland (SG) inflammatory lesions in Sjögren's syndrome (SS). However, their antigen specificity, degree of clonal expansion, and relationship to clinical disease features remain unknown. We used multiplex reverse-transcriptase PCR to amplify paired T cell receptor α (TCRα) and β transcripts of single CD4CD45RA T cells from SG and peripheral blood (PB) of 10 individuals with primary SS, 9 of whom shared the HLA DR3/DQ2 risk haplotype.

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

Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism.

Forward genetic screening identifies a small molecule that blocks Toxoplasma gondii growth by inhibiting both host- and parasite-encoded kinases.

The simultaneous targeting of host and pathogen processes represents an untapped approach for the treatment of intracellular infections. Hypoxia-inducible factor-1 (HIF-1) is a host cell transcription factor that is activated by and required for the growth of the intracellular protozoan parasite Toxoplasma gondii at physiological oxygen levels. Parasite activation of HIF-1 is blocked by inhibiting the family of closely related Activin-Like Kinase (ALK) host cell receptors ALK4, ALK5, and ALK7, which was determined in part by use of an ALK4,5,7 inhibitor named SB505124.

Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage.

Use of next-generation DNA sequencing to analyze genetic variants in rheumatic disease.

Next-generation DNA sequencing has revolutionized the field of genetics and genomics, providing researchers with the tools to efficiently identify novel rare and low frequency risk variants, which was not practical with previously available methodologies. These methods allow for the sequence capture of a specific locus or small genetic region all the way up to the entire six billion base pairs of the diploid human genome. Rheumatic diseases are a huge burden on the US population, affecting more than 46 million Americans.

Infinium assay for large-scale SNP genotyping applications.

Genotyping variants in the human genome has proven to be an efficient method to identify genetic associations with phenotypes. The distribution of variants within families or populations can facilitate identification of the genetic factors of disease. Illumina's panel of genotyping BeadChips allows investigators to genotype thousands or millions of single nucleotide polymorphisms (SNPs) or to analyze other genomic variants, such as copy number, across a large number of DNA samples.

Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations.

Recent reports have associated NCF2, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants.

BAC-pool sequencing and analysis of large segments of A12 and D12 homoeologous chromosomes in upland cotton.

Although new and emerging next-generation sequencing (NGS) technologies have reduced sequencing costs significantly, much work remains to implement them for de novo sequencing of complex and highly repetitive genomes such as the tetraploid genome of Upland cotton (Gossypium hirsutum L.). Herein we report the results from implementing a novel, hybrid Sanger/454-based BAC-pool sequencing strategy using minimum tiling path (MTP) BACs from Ctg-3301 and Ctg-465, two large genomic segments in A12 and D12 homoeologous chromosomes (Ctg).

An enhancer element harboring variants associated with systemic lupus erythematosus engages the TNFAIP3 promoter to influence A20 expression.

Functional characterization of causal variants present on risk haplotypes identified through genome-wide association studies (GWAS) is a primary objective of human genetics. In this report, we evaluate the function of a pair of tandem polymorphic dinucleotides, 42 kb downstream of the promoter of TNFAIP3, (rs148314165, rs200820567, collectively referred to as TT>A) recently nominated as causal variants responsible for genetic association of systemic lupus erythematosus (SLE) with tumor necrosis factor alpha inducible protein 3 (TNFAIP3). TNFAIP3 encodes the ubiquitin-editing enzyme, A20, a key negative regulator of NF-κB signaling.

WITHDRAWN: A female autoimmunity gene exists: DDX3X.

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RBPJ mutations identified in two families affected by Adams-Oliver syndrome.

Through exome resequencing, we identified two unique mutations in recombination signal binding protein for immunoglobulin kappa J (RBPJ) in two independent families affected by Adams-Oliver syndrome (AOS), a rare multiple-malformation disorder consisting primarily of aplasia cutis congenita of the vertex scalp and transverse terminal limb defects. These identified mutations link RBPJ, the primary transcriptional regulator for the Notch pathway, with AOS, a human genetic disorder. Functional assays confirmed impaired DNA binding of mutated RBPJ, placing it among other notch-pathway proteins altered in human genetic syndromes.

Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus.

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein.

Detection of members of the Secoviridae in the Tallgrass Prairie Preserve, Osage County, Oklahoma, USA.

Viruses are most frequently discovered because they cause disease. To expand knowledge of plant-associated viruses beyond these narrow constraints, non-cultivated plants of the Tallgrass Prairie of the United States were systematically surveyed for evidence of viruses. This report discusses putative viruses of the family Secoviridae identified by the survey.

Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study.

Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified.

The genomics of autoimmune disease in the era of genome-wide association studies and beyond.

Recent advances in the field of genetics have dramatically changed our understanding of autoimmune disease. Candidate gene and, more recently, genome-wide association (GWA) studies have led to an explosion in the number of loci and pathways known to contribute to autoimmune phenotypes. Since the 1970s, researchers have known that several alleles in the MHC region play a role in the pathogenesis of many autoimmune diseases.

Detection of members of the Tombusviridae in the Tallgrass Prairie Preserve, Osage County, Oklahoma, USA.

Viruses are most frequently discovered because they cause disease in organisms of importance to humans. To expand knowledge of plant-associated viruses beyond these narrow constraints, non-cultivated plants of the Tallgrass Prairie Preserve, Osage County, Oklahoma, USA were systematically surveyed for evidence of the presence of viruses. This report discusses viruses of the family Tombusviridae putatively identified by the survey.

Genome-wide DNA methylation maps in follicular lymphoma cells determined by methylation-enriched bisulfite sequencing.

Background: Follicular lymphoma (FL) is a form of non-Hodgkin's lymphoma (NHL) that arises from germinal center (GC) B-cells. Despite the significant advances in immunotherapy, FL is still not curable. Beyond transcriptional profiling and genomics datasets, there currently is no epigenome-scale dataset or integrative biology approach that can adequately model this disease and therefore identify novel mechanisms and targets for successful prevention and treatment of FL.

Ecogenomics: using massively parallel pyrosequencing to understand virus ecology.

Environmental samples have been analysed for viruses in metagenomic studies, but these studies have not linked individual viruses to their hosts. We designed a strategy to isolate double-stranded RNA, a hallmark of RNA virus infection, from individual plants and convert this to cDNA with a unique four nucleotide Tag at each end. Using 96 different Tags allowed us to pool samples and still retain the link to the original sample.

High-throughput sequence analysis of Ciona intestinalis SL trans-spliced mRNAs: alternative expression modes and gene function correlates.

Pre-mRNA 5' spliced-leader (SL) trans-splicing occurs in some metazoan groups but not in others. Genome-wide characterization of the trans-spliced mRNA subpopulation has not yet been reported for any metazoan. We carried out a high-throughput analysis of the SL trans-spliced mRNA population of the ascidian tunicate Ciona intestinalis by 454 Life Sciences (Roche) pyrosequencing of SL-PCR-amplified random-primed reverse transcripts of tailbud embryo RNA.