scholarly journals Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs and alternative-splicing events in systemic lupus erythematosus

2017 ◽  
pp. ddw417 ◽  
Author(s):  
Christopher A. Odhams ◽  
Andrea Cortini ◽  
Lingyan Chen ◽  
Amy L. Roberts ◽  
Ana Viñuela ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Alternative Splicing ◽  
Lupus Erythematosus ◽  
Susceptibility Genes ◽  
Rna Seq ◽  
Systemic Lupus ◽  
Non Coding Rnas ◽  
Alternative Splicing Events

scholarly journals Extensive Changes in Transcription Dynamics Reflected on Alternative Splicing Events in Systemic Lupus Erythematosus Patients

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1260
Author(s):  
Sofia Papanikolaou ◽  
George K. Bertsias ◽  
Christoforos Nikolaou
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Alternative Splicing ◽  
Lupus Erythematosus ◽  
Rna Splicing ◽  
Intron Retention ◽  
Mrna Translation ◽  
Sequencing Data ◽  
Systemic Lupus ◽  
Alternative Splicing Events ◽  
Transcriptional Output

In addition to increasing the complexity of the transcriptional output, alternative RNA splicing can lead to the reduction of mRNA translation or the production of non-functional or malfunctional proteins, thus representing a vital component of the gene regulation process. Herein, we set out to detect and characterize alternative splicing events that occur in whole-blood samples of patients with Systemic Lupus Erythematosus (SLE) as compared to healthy counterparts. Through the implementation of a computational pipeline on published RNA-sequencing data, we identified extensive changes in the transcription dynamics affecting a large number of genes. We found a predominance of intron retention events, with the majority introducing premature stop codons, suggestive of gene repression, in both inactive and active SLE patient samples. Alternative splicing affected a distinct set of genes from the ones detected as differentially expressed in the same comparisons, while alternatively spliced genes tended to reside in genome areas associated with increased gene co-expression. Functional analysis of genes affected by alternative splicing pointed towards particular functions related to metabolism and histone acetylation as of potential interest. Together, our findings underline the importance of incorporating alternative splicing analyses in the context of molecular characterization of complex diseases such as SLE.

scholarly journals Machine learning applied to whole-blood RNA-sequencing data uncovers distinct subsets of patients with systemic lupus erythematosus

2019 ◽  
Author(s):  
William A Figgett ◽  
Katherine Monaghan ◽  
Milica Ng ◽  
Monther Alhamdoosh ◽  
Eugene Maraskovsky ◽  
...  
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Systemic Lupus Erythematosus ◽  
Clinical Trials ◽  
Lupus Erythematosus ◽  
Whole Blood ◽  
Rna Seq ◽  
Systemic Lupus ◽  
Disease Heterogeneity ◽  
Healthy Donors

ABSTRACTObjectiveSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that is difficult to treat. There is currently no optimal stratification of patients with SLE, and thus responses to available treatments are unpredictable. Here, we developed a new stratification scheme for patients with SLE, based on the whole-blood transcriptomes of patients with SLE.MethodsWe applied machine learning approaches to RNA-sequencing (RNA-seq) datasets to stratify patients with SLE into four distinct clusters based on their gene expression profiles. A meta-analysis on two recently published whole-blood RNA-seq datasets was carried out and an additional similar dataset of 30 patients with SLE and 29 healthy donors was contributed in this research; 141 patients with SLE and 51 healthy donors were analysed in total.ResultsExamination of SLE clusters, as opposed to unstratified SLE patients, revealed underappreciated differences in the pattern of expression of disease-related genes relative to clinical presentation. Moreover, gene signatures correlated to flare activity were successfully identified.ConclusionGiven that disease heterogeneity has confounded research studies and clinical trials, our approach addresses current unmet medical needs and provides a greater understanding of SLE heterogeneity in humans. Stratification of patients based on gene expression signatures may be a valuable strategy to harness disease heterogeneity and identify patient populations that may be at an increased risk of disease symptoms. Further, this approach can be used to understand the variability in responsiveness to therapeutics, thereby improving the design of clinical trials and advancing personalised therapy.

scholarly journals Skewed allelic expression on X chromosome associated with aberrant expression of XIST on systemic lupus erythematosus lymphocytes

2020 ◽  
Vol 29 (15) ◽  
pp. 2523-2534 ◽  
Author(s):  
Yanfeng Zhang ◽  
Xinrui Li ◽  
Andrew Gibson ◽  
Jeffrey Edberg ◽  
Robert P Kimberly ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dna Methylation ◽  
X Chromosome ◽  
Lupus Erythematosus ◽  
Allelic Imbalance ◽  
Allelic Expression ◽  
Rna Seq ◽  
Systemic Lupus ◽  
Aberrant Expression ◽  
Adaptive Immune Cells

Abstract A common feature of autoimmune diseases, including systemic lupus erythematosus (SLE), is an increased prevalence in women. However, the molecular basis for sex disparity in SLE remains poorly understood. To examine the role of X-linked transcription in SLE adaptive immune cells, we performed RNA-seq in T cell and B cell subsets from either healthy donors or patients with SLE. Analyses of allelic expression (AE) profiles identified a pattern of increased allelic imbalance across the entire X chromosome in SLE lymphocytes. X-linked genes exhibiting AE in SLE had an extensive overlap with genes known to escape X chromosome inactivation (XCI). XIST RNA was overexpressed in SLE patients. Differential XIST expression correlated with AE profiles more positively at X-linked genes than the genome-wide background. Analysis of three independent RNA-seq data verified the XIST-associated skewed AE on X chromosome in SLE. Integrative analyses of DNA methylation profiles showed an increased variability of DNA methylation levels at these AE-related X-linked genes. In cultured lymphoblastic cells, knockdown of XIST specifically altered allelic imbalance patterns between X chromosomes. Our study provides genetic evidence that upregulation of XIST accompanied with more skewed allelic expression on X chromosome is associated with the pathogenesis of SLE and may provide mechanistic insights into the increased incidence of SLE in females.

Genetic analysis of complement C1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal C1s gene

2008 ◽  
Vol 45 (6) ◽  
pp. 1693-1702 ◽  
Author(s):  
Mariane T. Amano ◽  
Virgínia P.L. Ferriani ◽  
Marlene P.C. Florido ◽  
Edimara S. Reis ◽  
Maria I.M.V. Delcolli ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Alternative Splicing ◽  
Genetic Analysis ◽  
Lupus Erythematosus ◽  
Systemic Lupus

scholarly journals Aberrant Non-Coding RNA Expression in Patients with Systemic Lupus Erythematosus: Consequences for Immune Dysfunctions and Tissue Damage

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1641
Author(s):  
Chang-Youh Tsai ◽  
Chieh-Yu Shen ◽  
Chih-Wei Liu ◽  
Song-Chou Hsieh ◽  
Hsien-Tzung Liao ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Tissue Damage ◽  
Immune Modulation ◽  
Clinical Manifestations ◽  
Systemic Autoimmune Disease ◽  
Circular Rnas ◽  
Contributing Factors ◽  
Systemic Lupus ◽  
Non Coding Rnas

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with heterogeneous clinical manifestations. A diverse innate and adaptive immune dysregulation is involved in the immunopathogenesis of SLE. The dysregulation of immune-related cells may derive from the intricate interactions among genetic, epigenetic, environmental, and immunological factors. Of these contributing factors, non-coding RNAs (ncRNAs), including microRNAs (miRNAs, miRs), and long non-coding RNAs (lncRNAs) play critical roles in the post-transcriptional mRNA expression of cytokines, chemokines, and growth factors, which are essential for immune modulation. In the present review, we emphasize the roles of ncRNA expression in the immune-related cells and cell-free plasma, urine, and tissues contributing to the immunopathogenesis and tissue damage in SLE. In addition, the circular RNAs (circRNA) and their post-translational regulation of protein synthesis in SLE are also briefly described. We wish these critical reviews would be useful in the search for biomarkers/biosignatures and novel therapeutic strategies for SLE patients in the future.

scholarly journals Role of MHC-Linked Susceptibility Genes in the Pathogenesis of Human and Murine Lupus

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Manfred Relle ◽  
Andreas Schwarting
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Association Studies ◽  
Susceptibility Genes ◽  
Genome Wide Association Studies ◽  
Systemic Lupus ◽  
Nuclear Antigens ◽  
Genome Wide ◽  
Conventional Drug

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies against nuclear antigens and a systemic inflammation that can damage a broad spectrum of organs. SLE patients suffer from a wide variety of symptoms, which can affect virtually almost any tissue. As lupus is difficult to diagnose, the worldwide prevalence of SLE can only be roughly estimated to range from 10 and 200 cases per 100,000 individuals with dramatic differences depending on gender, ethnicity, and location. Although the treatment of this disease has been significantly ameliorated by new therapies, improved conventional drug therapy options, and a trained expert eye, the underlying pathogenesis of lupus still remain widely unknown. The complex etiology reflects the complex genetic background of the disease, which is also not well understood yet. However, in the past few years advances in lupus genetics have been made, notably with the publication of genome-wide association studies (GWAS) in humans and the identification of susceptibility genes and loci in mice. This paper reviews the role of MHC-linked susceptibility genes in the pathogenesis of systemic lupus erythematosus.

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