RNA-Seq profiling of leukocytes reveals a sex-dependent global circular RNA upregulation in multiple sclerosis and 6 candidate biomarkers

2020 ◽  
Vol 29 (20) ◽  
pp. 3361-3372
Author(s):  
Leire Iparraguirre ◽  
Ainhoa Alberro ◽  
Lucía Sepúlveda ◽  
Iñaki Osorio-Querejeta ◽  
Laura Moles ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Differential Expression Analysis ◽  
Area Under The Curve ◽  
Circular Rna ◽  
Circular Rnas ◽  
Rna Seq ◽  
Paired Samples ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease ◽  
Diagnosis Classification

Abstract Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, with higher prevalence in women, that leads to neurological disability. The disease course and clinical phenotype are highly variable, and therefore, biomarkers for the diagnosis, classification, monitoring of the disease and treatment assessment are needed. Studies have shown a dysregulation in the coding and non-coding RNAs and proposed some as biomarkers. However, still none of them have reached the clinical practice. Recently, circular RNAs (circRNAs) have emerged as new players in the transcriptome that hold a great potential as biomarkers in several diseases. Leukocytes from 30 MS patients and 20 healthy controls (HCs) were RNA-sequenced to study the linear and circular transcriptome. Differential expression analysis was performed by DESeq, and circRNA candidates were studied in a second cohort (70 MS and 46 HC) by RT-qPCR and in paired samples drawn during the relapse and remission phases (20 patients). Among the differentially expressed circRNAs, 96.1% are upregulated in patients compared with controls, but similar circRNA profiles are found between MS types. The same upregulation trend was observed in females but not in males or in the linear transcriptome. The upregulation of 6 circRNAs was validated, and a change in their expression was found between relapse and remission. The 6 circRNAs showed a good performance to discriminate patients from HC with a combined area under the curve of 0.852. There is global, specific and sex-dependent increase of circRNA expression in MS, and 6 circRNAs are proposed as potential biomarkers.

scholarly journals DEBKS: A Tool to Detect Differentially Expressed Circular RNA

2020 ◽  
Author(s):  
Zelin Liu ◽  
Huiru Ding ◽  
Jianqi She ◽  
Chunhua Chen ◽  
Weiguang Zhang ◽  
...  
Keyword(s):  
Open Source ◽  
Rna Sequencing ◽  
Open Source Software ◽  
Simulated Data ◽  
Circular Rna ◽  
Host Gene ◽  
Circular Rnas ◽  
Biological Processes ◽  
Rna Seq ◽  
Disease Pathogenesis

AbstractCircular RNAs (circRNAs) are involved in various biological processes and in disease pathogenesis. However, only a small number of functional circRNAs have been identified among hundreds of thousands of circRNA species, partly because most current methods are based on circular junction counts and overlook the fact that circRNA is formed from the host gene by back-splicing (BS). To distinguish between expression originating from BS and that from the host gene, we present DEBKS, a software program to streamline the discovery of differential BS between two rRNA-depleted RNA sequencing (RNA-seq) sample groups. By applying real and simulated data and employing RT-qPCR for validation, we demonstrate that DEBKS is efficient and accurate in detecting circRNAs with differential BS events between paired and unpaired sample groups. DEBKS is available at https://github.com/yangence/DEBKS as open-source software.

scholarly journals Genetic Variant rs755622 Regulates Expression of the Multiple Sclerosis Severity Modifier D-Dopachrome Tautomerase in a Sex-Specific Way

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Zhijie Han ◽  
Jiaojiao Qu ◽  
Jiehong Zhao ◽  
Xiao Zou
Keyword(s):  
Multiple Sclerosis ◽  
Macrophage Migration Inhibitory Factor ◽  
Large Scale ◽  
Genetic Variant ◽  
Differential Expression Analysis ◽  
Promoter Sequence ◽  
Minor Allele ◽  
Rna Seq ◽  
Dopachrome Tautomerase ◽  
Allele Variant

Multiple sclerosis (MS) is a sex-specific autoimmune disease involving central nervous system. Previous studies determined that macrophage migration inhibitory factor (MIF) and its homologue D-dopachrome tautomerase (DDT) sex-specifically affect MS progression. Moreover, other studies reported that rs755622 polymorphism in promoter region of MIF gene is associated with risk of MS and affects the promoter activity to regulate MIF expression in a sex-specific way. Given that MIF and DDT share a part of promoter sequence, we surmise that rs755622 can also regulate DDT expression in a sex-specific way. However, this has not yet been studied. Here, we used five large-scale expression quantitative trait loci (eQTLs) and two RNA-seq datasets from brain and blood to assess the potential influence of rs755622 variant on expression of DDT in different genders by the linear regression and differential expression analysis. The results show that the minor allele frequency of rs755622 and expression of DDT are significantly increased in males for MS subjects and this minor allele variant can significantly upregulate DDT expression for males but not females, which suggests that the regulation of DDT expression level by rs755622 can affect MS progression in males. These findings further support and expand conclusions of previous studies and may help to better understand the mechanisms of MS.

scholarly journals Circulating Circular RNAs as Biomarkers for the Diagnosis and Prediction of Outcomes in Acute Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (1) ◽  
pp. 319-323 ◽  
Author(s):  
Lei Zuo ◽  
Lin Zhang ◽  
Juan Zu ◽  
Zan Wang ◽  
Bing Han ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Quantitative Polymerase Chain Reaction ◽  
Area Under The Curve ◽  
Circular Rna ◽  
Population Based ◽  
Circular Rnas ◽  
Healthy Controls ◽  
Change Rate ◽  
Stroke Outcomes

Background and Purpose— Circular RNAs (CircRNAs) show promise as stroke biomarkers because of their participation in various pathophysiological processes associated with acute ischemic stroke (AIS) and stability in peripheral blood. Methods— A circRNA microarray was used to identify differentially expressed circulating circRNAs in a discovery cohort (3 versus 3). Validation (36 versus 36) and replication (200 versus 100) were performed in independent cohorts by quantitative polymerase chain reaction. Platelets, lymphocytes, and granulocytes were separated from blood to examine the origins of circRNAs. Results— There were 3 upregulated circRNAs in Chinese population–based AIS patients compared with healthy controls. The combination of 3 circRNAs resulted in an area under the curve of 0.875, corresponding to a specificity of 91% and a sensitivity of 71.5% in AIS diagnosis. Furthermore, the combination of change rate in 3 circRNAs within the first 7 days of treatment showed an area under the curve of 0.960 in predicting stroke outcome. There was significant increase in lymphocytes and granulocytes for circPDS5B (circular RNA PDS5B) and only in granulocytes for circCDC14A (circular RNA CDC14A) in AIS patients compared with healthy controls. Conclusions— Three circRNAs could serve as biomarkers for AIS diagnosis and prediction of stroke outcomes. The elevated levels of circPDS5B and circCDC14A after stroke might be because of increased levels in lymphocytes and granulocytes.

scholarly journals The Landscape of MicroRNA, Piwi-Interacting RNA, and Circular RNA in Human Saliva

2015 ◽  
Vol 61 (1) ◽  
pp. 221-230 ◽  
Author(s):  
Jae Hoon Bahn ◽  
Qing Zhang ◽  
Feng Li ◽  
Tak-Ming Chan ◽  
Xianzhi Lin ◽  
...  
Keyword(s):  
Body Fluid ◽  
Expression Profiles ◽  
Embryonic Stem ◽  
Bioinformatic Analysis ◽  
Circular Rna ◽  
Human Saliva ◽  
Body Fluids ◽  
Individual Variability ◽  
Circular Rnas ◽  
Rna Seq

Abstract BACKGROUND Extracellular RNAs (exRNAs) in human body fluids are emerging as effective biomarkers for detection of diseases. Saliva, as the most accessible and noninvasive body fluid, has been shown to harbor exRNA biomarkers for several human diseases. However, the entire spectrum of exRNA from saliva has not been fully characterized. METHODS Using high-throughput RNA sequencing (RNA-Seq), we conducted an in-depth bioinformatic analysis of noncoding RNAs (ncRNAs) in human cell-free saliva (CFS) from healthy individuals, with a focus on microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), and circular RNAs (circRNAs). RESULTS Our data demonstrated robust reproducibility of miRNA and piRNA profiles across individuals. Furthermore, individual variability of these salivary RNA species was highly similar to those in other body fluids or cellular samples, despite the direct exposure of saliva to environmental impacts. By comparative analysis of >90 RNA-Seq data sets of different origins, we observed that piRNAs were surprisingly abundant in CFS compared with other body fluid or intracellular samples, with expression levels in CFS comparable to those found in embryonic stem cells and skin cells. Conversely, miRNA expression profiles in CFS were highly similar to those in serum and cerebrospinal fluid. Using a customized bioinformatics method, we identified >400 circRNAs in CFS. These data represent the first global characterization and experimental validation of circRNAs in any type of extracellular body fluid. CONCLUSIONS Our study provides a comprehensive landscape of ncRNA species in human saliva that will facilitate further biomarker discoveries and lay a foundation for future studies related to ncRNAs in human saliva.

scholarly journals Plasma complement biomarkers distinguish multiple sclerosis and neuromyelitis optica spectrum disorder

2016 ◽  
Vol 23 (7) ◽  
pp. 946-955 ◽  
Author(s):  
Svetlana Hakobyan ◽  
Sebastian Luppe ◽  
David RS Evans ◽  
Katharine Harding ◽  
Samantha Loveless ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neuromyelitis Optica ◽  
Unmet Need ◽  
Area Under The Curve ◽  
Spectrum Disorder ◽  
Demyelinating Diseases ◽  
Neuromyelitis Optica Spectrum Disorder ◽  
Complement Proteins ◽  
Activation Products ◽  
The Central Nervous System

Background: Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are autoimmune inflammatory demyelinating diseases of the central nervous system. Although distinguished by clinicoradiological and demographic features, early manifestations can be similar complicating management. Antibodies against aquaporin-4 support the diagnosis of NMOSD but are negative in some patients. Therefore, there is unmet need for biomarkers that enable early diagnosis and disease-specific intervention. Objective: We investigated whether plasma complement proteins are altered in MS and NMOSD and provide biomarkers that distinguish these diseases. Methods: Plasma from 54 NMOSD, 40 MS and 69 control donors was tested in multiplex assays measuring complement activation products and proteins. Using logistic regression, we tested whether combinations of complement analytes distinguished NMOSD from controls and MS. Results: All activation products were elevated in NMOSD compared to either control or MS. Four complement proteins (C1inh, C1s, C5 and FH) were higher in NMOSD compared to MS or controls. A model comprising C1inh and terminal complement complex (TCC) distinguished NMOSD from MS (area under the curve (AUC): 0.98), while C1inh and C5 distinguished NMOSD from controls (AUC: 0.94). Conclusion: NMOSD is distinguished from MS by plasma complement biomarkers. Selected complement analytes enable differential diagnosis. Findings support trials of anti-complement therapies in NMOSD.

scholarly journals Disrupted microglial iron homeostasis in progressive multiple sclerosis

2021 ◽  
Author(s):  
Dimitry Ofengeim ◽  
Jonathan D Proto ◽  
Mindy Zhang ◽  
Sean Ryan ◽  
Xinting Yao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Iron Homeostasis ◽  
Clinical Symptoms ◽  
Cell Types ◽  
Progressive Multiple Sclerosis ◽  
Post Mortem Brain ◽  
The Central Nervous System ◽  
Single Nucleus ◽  
Multiple Cell ◽  
Chronic Autoimmune Disease

Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS). Despite therapies that reduce relapses, many patients eventually develop secondary progressive MS (SPMS), characterized by ongoing and irreversible neurodegeneration and worsening clinical symptoms. Microglia are the resident innate immune cells of the CNS. While the cellular and molecular determinants of disability progression in MS remain incompletely understood, they are thought to include non resolving microglial activation and chronic oxidative injury. In this study, our aim was to better characterize microglia in SPMS tissues to identify disease-related changes at the single cell level. We performed single nucleus RNA-seq (snRNA-seq) on cryopreserved post-mortem brain cortex and identified disease associated changes in multiple cell types and in particular distinct SPMS enriched microglia subsets. When compared to the cluster most enriched in healthy controls (i.e. homeostatic microglia), we found a number of SPMS-enriched clusters with transcriptional profiles reflecting increased oxidative stress and perturbed iron homeostasis. Using histology and RNA-scope, we confirmed the presence of iron accumulating, ferritin-light chain (FTL)-expressing microglia in situ. Among disease-enriched clusters, we found evidence for divergent responses to iron accumulation and identified the antioxidant enzyme GPX as a key fate determinant. These data help elucidate processes that occur in progressive MS brains, and highlight novel nodes for therapeutic intervention.

scholarly journals Small RNA-Seq reveals novel miRNAs shaping the transcriptomic identity of rat brain structures

2018 ◽  
Vol 1 (5) ◽  
pp. e201800018 ◽  
Author(s):  
Anaïs Soula ◽  
Mélissa Valere ◽  
María-José López-González ◽  
Vicky Ury-Thiery ◽  
Alexis Groppi ◽  
...  
Keyword(s):  
Small Rna ◽  
Critical Role ◽  
Differential Expression Analysis ◽  
Brain Structures ◽  
Strong Impact ◽  
The Novel ◽  
Rna Seq ◽  
Functional Identities ◽  
The Central Nervous System ◽  
Rat Cns

In the central nervous system (CNS), miRNAs are involved in key functions, such as neurogenesis and synaptic plasticity. Moreover, they are essential to define specific transcriptomes in tissues and cells. However, few studies were performed to determine the miRNome of the different structures of the rat CNS, although a major model in neuroscience. Here, we determined by small RNA-Seq, the miRNome of the olfactory bulb, the hippocampus, the cortex, the striatum, and the spinal cord and showed the expression of 365 known miRNAs and 90 novel miRNAs. Differential expression analysis showed that several miRNAs were specifically enriched/depleted in these CNS structures. Transcriptome analysis by mRNA-Seq and correlation based on miRNA target predictions suggest that the specifically enriched/depleted miRNAs have a strong impact on the transcriptomic identity of the CNS structures. Altogether, these results suggest the critical role played by these enriched/depleted miRNAs, in particular the novel miRNAs, in the functional identities of CNS structures.

scholarly journals Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data

2021 ◽  
Vol 12 ◽  
Author(s):  
Yijie He ◽  
Lin Huang ◽  
Yaqin Tang ◽  
Zeyuan Yang ◽  
Zhijie Han
Keyword(s):  
Multiple Sclerosis ◽  
Transcription Initiation ◽  
Gene Interaction ◽  
Initiation Site ◽  
Rna Seq ◽  
Average Percentage ◽  
Genome Wide ◽  
Variant Genotype ◽  
Demyelinating Lesions ◽  
The Central Nervous System

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelinating lesions in the central nervous system. Recently, the dysregulation of alternative splicing (AS) in the brain has been found to significantly influence the progression of MS. Moreover, previous studies demonstrate that many MS-related variants in the genome act as the important regulation factors of AS events and contribute to the pathogenesis of MS. However, by far, no genome-wide research about the effect of genomic variants on AS events in MS has been reported. Here, we first implemented a strategy to obtain genomic variant genotype and AS isoform average percentage spliced-in values from RNA-seq data of 142 individuals (51 MS patients and 91 controls). Then, combing the two sets of data, we performed a cis-splicing quantitative trait loci (sQTLs) analysis to identify the cis-acting loci and the affected differential AS events in MS and further explored the characteristics of these cis-sQTLs. Finally, the weighted gene coexpression network and gene set enrichment analyses were used to investigate gene interaction pattern and functions of the affected AS events in MS. In total, we identified 5835 variants affecting 672 differential AS events. The cis-sQTLs tend to be distributed in proximity of the gene transcription initiation site, and the intronic variants of them are more capable of regulating AS events. The retained intron AS events are more susceptible to influence of genome variants, and their functions are involved in protein kinase and phosphorylation modification. In summary, these findings provide an insight into the mechanism of MS.

scholarly journals Circall: fast and accurate methodology for discovery of circular RNAs from paired-end RNA-sequencing data

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Dat Thanh Nguyen ◽  
Quang Thinh Trac ◽  
Thi-Hau Nguyen ◽  
Ha-Nam Nguyen ◽  
Nir Ohad ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Simulated Data ◽  
High Sensitivity ◽  
Circular Rna ◽  
Computational Time ◽  
Circular Rnas ◽  
Rna Seq ◽  
Sequencing Data ◽  
Mapping Algorithm ◽  
False Discovery Rate Method

Abstract Background Circular RNA (circRNA) is an emerging class of RNA molecules attracting researchers due to its potential for serving as markers for diagnosis, prognosis, or therapeutic targets of cancer, cardiovascular, and autoimmune diseases. Current methods for detection of circRNA from RNA sequencing (RNA-seq) focus mostly on improving mapping quality of reads supporting the back-splicing junction (BSJ) of a circRNA to eliminate false positives (FPs). We show that mapping information alone often cannot predict if a BSJ-supporting read is derived from a true circRNA or not, thus increasing the rate of FP circRNAs. Results We have developed Circall, a novel circRNA detection method from RNA-seq. Circall controls the FPs using a robust multidimensional local false discovery rate method based on the length and expression of circRNAs. It is computationally highly efficient by using a quasi-mapping algorithm for fast and accurate RNA read alignments. We applied Circall on two simulated datasets and three experimental datasets of human cell-lines. The results show that Circall achieves high sensitivity and precision in the simulated data. In the experimental datasets it performs well against current leading methods. Circall is also substantially faster than the other methods, particularly for large datasets. Conclusions With those better performances in the detection of circRNAs and in computational time, Circall facilitates the analyses of circRNAs in large numbers of samples. Circall is implemented in C++ and R, and available for use at https://www.meb.ki.se/sites/biostatwiki/circall and https://github.com/datngu/Circall.

scholarly journals Multiple Sclerosis

2020 ◽  
Author(s):  
Amirhossein Azari Jafari ◽  
Seyyedmohammadsadeq Mirmoeeni
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Optic Nerve ◽  
Autoimmune Disease ◽  
The Central Nervous System ◽  
Genetic And Environmental Factors ◽  
Chronic Autoimmune Disease ◽  
The Brain

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS), caused by genetic and environmental factors. It is characterized by intermittent and recurrent episodes of inflammation that result in the demyelination and subsequent damage of the underlying axons present in the brain, optic nerve and spinal cord [1][2][3].

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