Scavenging the hidden impacts of non-coding RNAs in multiple sclerosis

Elkhodiry, Aya A.; Tayebi, H.M. El

doi:10.1016/j.ncrna.2021.12.002

Cited by 8 publications

(4 citation statements)

References 138 publications

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“…Epigenetic research has garnered rightful interest in its contribution to understanding disease pathology ( 20 ), susceptibility, and development ( 20 ). Several areas of research have recently taken interest in the roles of lncRNAs in immune-mediated diseases in general, and MS in particular, in light of the pre-established epigenetic changes that are observed in the disease pathology ( 8 – 11 ).…”

Section: Discussionmentioning

confidence: 99%

Rs205764 and rs547311 in linc00513 may influence treatment responses in multiple sclerosis patients: A pharmacogenomics Egyptian study

Amin

El-Aziz²,

Hamed³

et al. 2023

Front. Immunol.

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BackgroundMultiple sclerosis (MS) is characterized by a complex etiology that is reflected in the lack of consistently predictable treatment responses across patients of seemingly similar characteristics. Approaches to demystify the underlying predictors of aberrant treatment responses have made use of genome-wide association studies (GWAS), with imminent progress made in identifying single nucleotide polymorphisms (SNPs) associated with MS risk, disease progression, and treatment response. Ultimately, such pharmacogenomic studies aim to utilize the approach of personalized medicine to maximize patient benefit and minimize rate of disease progression.ObjectiveVery limited research is available around the long intergenic non-coding RNA (linc)00513, recently being reported as a novel positive regulator of the type-1 interferon (IFN) pathway, following its overexpression in the presence of two polymorphisms: rs205764 and rs547311 in the promoter region of this gene. We attempt to provide data on the prevalence of genetic variations at rs205764 and rs547311 in Egyptian MS patients, and correlate these polymorphisms with the patients’ responses to disease-modifying treatments.MethodsGenomic DNA from 144 RRMS patients was isolated and analyzed for genotypes at the positions of interest on linc00513 using RT-qPCR. Genotype groups were compared with regards to their response to treatment; additional secondary clinical parameters including the estimated disability status score (EDSS), and onset of the disease were examined in relation to these polymorphisms.ResultsPolymorphisms at rs205764 were associated with a significantly higher response to fingolimod and a significantly lower response to dimethylfumarate. Moreover, the average EDSS of patients carrying polymorphisms at rs547311 was significantly higher, whereas no correlation appeared to exist with the onset of MS.ConclusionUnderstanding the complex interplay of factors influencing treatment response is pivotal in MS. One of the factors contributing to a patient’s response to treatment, as well as disease disability, may be polymorphisms on non-coding genetic material, such as rs205764 and rs547311 on linc00513. Through this work, we propose that genetic polymorphisms may partially drive disease disability and inconsistent responses to treatment in MS; we also aim to draw attention towards genetic approaches, such as screening for specific polymorphisms, to possibly direct treatment choices in such a complex disease.

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Section: Discussionmentioning

confidence: 99%

Rs205764 and rs547311 in linc00513 may influence treatment responses in multiple sclerosis patients: A pharmacogenomics Egyptian study

Amin

El-Aziz²,

Hamed³

et al. 2023

Front. Immunol.

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“…Three of these ncRNAs (LOC124905722, LOC124906211, and LOC124907546) were upregulated in brain lesions but downregulated in immune cells, while one (LOC124907109) was downregulated in both datasets. ncRNAs have been a subject of intense research in recent MS studies [43][44][45][46]. The observed pattern of upregulation in brain lesions and downregulation in immune cells suggests a disturbed regulation of ncRNA expression in MS.…”

Section: Multiple Sclerosismentioning

confidence: 99%

Transcriptome driven discovery of novel candidate genes for human neurological disorders in the telomer-to-telomer genome assembly era

Falker-Gieske

2023

Hum Genomics

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Background With the first complete draft of a human genome, the Telomere-to-Telomere Consortium unlocked previously concealed genomic regions for genetic analyses. These regions harbour nearly 2000 potential novel genes with unknown function. In order to uncover candidate genes associated with human neurological pathologies, a comparative transcriptome study using the T2T-CHM13 and the GRCh38 genome assemblies was conducted on previously published datasets for eight distinct human neurological disorders. Results The analysis of differential expression in RNA sequencing data led to the identification of 336 novel candidate genes linked to human neurological disorders. Additionally, it was revealed that, on average, 3.6% of the differentially expressed genes detected with the GRCh38 assembly may represent potential false positives. Among the noteworthy findings, two novel genes were discovered, one encoding a pore-structured protein and the other a highly ordered β-strand-rich protein. These genes exhibited upregulation in multiple epilepsy datasets and hold promise as candidate genes potentially modulating the progression of the disease. Furthermore, an analysis of RNA derived from white matter lesions in multiple sclerosis patients indicated significant upregulation of 26 rRNA encoding genes. Additionally, putative pathology related genes were identified for Alzheimer’s disease, amyotrophic lateral sclerosis, glioblastoma, glioma, and conditions resulting from the m.3242 A > G mtDNA mutation. Conclusion The results presented here underline the potential of the T2T-CHM13 assembly in facilitating the discovery of candidate genes from transcriptome data in the context of human disorders. Moreover, the results demonstrate the value of remapping sequencing data to a superior genome assembly. Numerous potential pathology related genes, either as causative factors or related elements, have been unveiled, warranting further experimental validation.

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“…Altered ncRNAs can interfere with the correct expression or splicing of specific target genes and can also affect protein functionality 13–15 . In the context of central nervous system autoimmunity, several microRNAs and lncRNAs have been found to be dysregulated in different immune and neuronal cell populations from patients with MS and experimental autoimmune encephalomyelitis models 16,17 …”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15] In the context of central nervous system autoimmunity, several microRNAs and lncRNAs have been found to be dysregulated in different immune and neuronal cell populations from patients with MS and experimental autoimmune encephalomyelitis models. 16,17 Here, we used whole RNA-seq technology to provide the first bona fide description of the ataxin-1-associated ncRNA repertoire in B cells upon an encephalitogenic challenge. Distinct transcriptomic signatures were identified in Atxn1-null mice, with enrichment of processed pseudogenes and intergenic lncRNAs, respectively, at baseline and 10 days after experimental autoimmune encephalomyelitis immunization.…”

Section: Introductionmentioning

confidence: 99%

Ataxin‐1 controls the expression of specific noncoding RNAs in B cells upon autoimmune demyelination

Didonna

2023

Immunol Cell Biol

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B cells play a key mechanistic role in the pathogenesis of multiple sclerosis (MS), a chronic neurological disease of the central nervous system with an autoimmune etiology. B cells contribute to disease initiation and progression by acting as professional antigen-presenting cells as well as via secreting autoantibodies and proinflammatory cytokines. We have recently shown that the polyglutamine protein ataxin-1, which was first linked to the movement disorder spinocerebellar ataxia type 1, also acts as a master regulator of B-cell functions in the context of central nervous system autoimmunity. In fact, ataxin-1-deficient mice display an aggravated manifestation of the MS disease model experimental autoimmune encephalomyelitis along with aberrant B-cell functions. Consistent with this scenario, transcriptomic analysis of Atxn1-null B cells highlighted distinct genetic signatures involved in cell activation, proliferation and antigen presentation. To further characterize the role of ataxin-1, we profiled the noncoding transcriptome controlled by ataxin-1 in the B-cell compartment upon an encephalitogenic challenge. We show that two specific classes of noncoding RNAs, namely, processed pseudogenes and intergenic long noncoding RNAs, are differentially regulated along disease. Furthermore, pathway and protein network analyses on their putative proteincoding gene targets found a significant enrichment in ontologies related to cell mitosis, together with molecular processes relevant to MS such as chitin metabolism. Altogether, these findings shed light on the possible contribution of noncoding RNAs to B-cell biology and MS pathogenesis, and further establish the immunomodulatory role of ataxin-1 in autoimmune demyelination.

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Scavenging the hidden impacts of non-coding RNAs in multiple sclerosis

Cited by 8 publications

References 138 publications

Rs205764 and rs547311 in linc00513 may influence treatment responses in multiple sclerosis patients: A pharmacogenomics Egyptian study

Rs205764 and rs547311 in linc00513 may influence treatment responses in multiple sclerosis patients: A pharmacogenomics Egyptian study

Transcriptome driven discovery of novel candidate genes for human neurological disorders in the telomer-to-telomer genome assembly era

Ataxin‐1 controls the expression of specific noncoding RNAs in B cells upon autoimmune demyelination

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