Small non-coding RNA profiling across cellular and biofluid compartments and their implications for multiple sclerosis immunopathology
To improve our understanding of MS pathology and heterogeneity and provide new strategies for biomarkers and treatments development we carried out a genome-wide small non-coding RNA analysis. The analysis was performed in paired peripheral blood mononuclear cells, plasma, cerebrospinal fluid (CSF) cells and cell-free CSF from 29 MS patients and 16 controls using next-generation sequencing. We aimed to detect differentially expressed small non-coding RNAs between MS and controls. The data contains unique molecular identifier (UMI) count information for each transcript. The small non-coding RNA analysis was performed in paired peripheral blood mononuclear cells, plasma, cerebrospinal fluid (CSF) cells and cell-free CSF from 29 MS patients and 16 controls using next-generation sequencing. One INDC control was missing a CSF cell and cell-free CSF sample and one NINDC control was missing a PBMC and plasma sample. Small non-coding RNAs were isolated from 300 ul of plasma or CSF using the miRCURY RNA isolation kit for biofluids (Exiqon, Denmark) or from CSF cells and peripheral blood mononuclear cells precipitate using the miRNAeasy micro kit (Qiagen, Germany). Small non-coding RNA libraries were prepared as previously described at PMID: 27798564. The libraries were sequenced on eight lanes of HiSeq2500. Preprocessing and alignment were done according to PMID: 30250291. The "Unique molecular identifier_sncRNAs_analysis_MS" file contains unique molecular identifier count information for each small non-coding RNA transcript as well as other types of transcripts identified in the sequencing libraries from 44 individuals and 4 compartments (PBMCs, CSF cells, plasma, cell-free CSF). Altogether 176 samples. The metafile contains information about the disease status, sex, age for all MS patients and controls. The "readme" explains the contents of the data files and contains the variables list.
Profiling of small non-coding RNAs across cellular and biofluid compartments: implications for multiple sclerosis immunopathology. Galina Yurevna Zheleznyakova, Eliane Piket, Maria Needhamsen, Michael Hagemann-Jensen, Diana Ekman, Mohsen Khademi, Faiez Al Nimer, Patrick Scicluna, Omid R Faridani, Tomas Olsson, Fredrik Piehl, Maja Jagodic. Deposited on bioRxiv. https://www.biorxiv.org/content/10.1101/2020.05.15.097519v1
Zheleznyakova, G. Y., Piket, E., Needhamsen, M., Hagemann-Jensen, M., Ekman, D., Han, Y., James, T., Khademi, M., Al Nimer, F., Scicluna, P., Zheleznyakova, G., Piket, E., Needhamsen, M., Hagemann-Jensen, M., Ekman, D., Han, Y., James, T., Khademi, M., Al, N. F., … Jagodic, M. (2021). Small noncoding RNA profiling across cellular and biofluid compartments and their implications for multiple sclerosis immunopathology. In PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (Vol. 118, Issue 17). https://doi.org/10.1073/pnas.2011574118
National Bioinformatics Infrastructure Sweden
Swedish Association of persons with Neurological disabilities
AstraZeneca-Science for Life Laboratory collaboration
Genetics and Pathogenesis of neuroinflammation with a focus on Multiple Sclerosis
In multiple sclerosis (MS), inflammatory cells from the blood periodically enter the central nervous system, where they cause damage to nerve tracts and neurological deficits. With time, MS becomes progressive with increasing disabilities. Current treatments are risky because they strike broadly in the immune system, and there are no therapies for the progressive phase. The etiology of MS involves both genetic predisposition and lifestyle/environmental factors, thus logically targets for studies.The overall aim is to understand the causes, pathogenesis and severity/progression of MS by studies in very large, nation-wide, MS case-control materials, integrated with molecular genetics and functional studies in materials from humans and in rodent models of MS. The project is multidisciplinary and relies on intensive local, national and international collaborations.We will: 1) Define gene loci, lifestyle/environmental factors and pathways that drive severity/progression, in addition to MS risk alone. 2) Decipher MS risk gene-environment interactions. We have shown that such interactions are potent, and we are world-wide leading these attempts. 3) Define the function of selected MS gene loci. 4) Define the disease relevant T cell specificities with a new technology. 5) Study the mechanisms of selected genes/loci regulating mouse and rat MS mimicking models.The project can lead to a better prevention, and to a basis for more precise treatment during the different phases of MS.
Epigenetics of Multiple Sclerosis: towards a better understanding of pathogenic mechanisms and improved disease management
Multiple Sclerosis (MS) is a leading cause of incurable progressive neurological disability in young adults. We propose that epigenetic mechanisms such as DNA methylation, that regulate gene expression without affecting the genetic code, mediate the processes that cause MS and that aberrant epigenetic states can be corrected to develop alternative therapeutic modalities.We will exploit the stable and reversible nature of DNA methylation to: (i) Identify novel modifiable mechanisms that trigger MS and predispose for disease progression, (ii) Develop alternative therapeutic strategies based on reversing causal epigenetic states, and (iii) Characterize epigenetic marks that can serve as specific biomarkers. Our unique MS biobank combined with cutting-edge methodologies to capture relevant cells and measure their functional states from the full methylome and transcriptome data provides a starting point to identify aberrant epigenetic changes in MS. This will be complemented with studies of the functional impact of these changes using innovative in vitro epigenome screens. We will then utilize in vivo animal models to dissect their molecular mechanisms and test the therapeutic potential of targeted epigenome editing.Our findings may set the stage for a paradigm-shift in studying and treating chronic diseases based on preventing and modulating aggressive immune responses and promoting brain tissue repair through inducing self-sustained reversal of aberrant epigenetic states.
An epigenomic approach to identify key drivers of chronic inflammation and neuronal loss in Multiple Sclerosis
Predisposition to common diseases irrefutably depends on the complex interplay between genes and environmental factors. Despite the fact that epigenetic mechanisms (e.g. DNA methylation) control gene expression following instructions from the genome and environment, they are still virtually unexplored in diseases such as Multiple Sclerosis (MS). We will (i) exploit epigenetic changes to learn more about the mechanisms that mediate effects of genetic and environmental factors in etiology of MS; (ii) characterize epigenetic changes that control ´aggressiveness´ of the pathogenic cells (CD4+ T cells and monocytes) and ´vulnerability´ of the target cells (neurons); (iii) define functional mechanisms of the most interesting changes; and (iv) investigate if the obtained knowledge can be used for better biomarkers and novel treatments. We will utilize unique and world-renowned clinical cohorts in combination with state-of-the-art methods to measure DNA methylation and transcription in discrete cell types, followed by functional studies in experimental models. The vital difference between genetics and epigenetics lies in the fact that epigenetic states are reversible and it is possible to alter unfavorable state towards recovery. Therefore, characterizing epigenetic mechanisms gives tremendous opportunities for better understanding and management of MS and can have important implications for other diseases with similar complex etiologies.
An autoimmune disorder mainly affecting young adults and characterized by destruction of myelin in the central nervous system. Pathologic findings include multiple sharply demarcated areas of demyelination throughout the white matter of the central nervous system. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction. The usual pattern is one of recurrent attacks followed by partial recovery (see MULTIPLE SCLEROSIS, RELAPSING-REMITTING), but acute fulminating and chronic progressive forms (see MULTIPLE SCLEROSIS, CHRONIC PROGRESSIVE) also occur. (Adams et al., Principles of Neurology, 6th ed, p903)
The most common clinical variant of MULTIPLE SCLEROSIS, characterized by recurrent acute exacerbations of neurologic dysfunction followed by partial or complete recovery. Common clinical manifestations include loss of visual (see OPTIC NEURITIS), motor, sensory, or bladder function. Acute episodes of demyelination may occur at any site in the central nervous system, and commonly involve the optic nerves, spinal cord, brain stem, and cerebellum. (Adams et al., Principles of Neurology, 6th ed, pp903-914)
Multiple Sclerosis, Secondary-Progressive
data/Unique molecular identifiers_sncRNAs_analysis_MS.txt
data/Unique molecular identifiers_sncRNAs_analysis_MS.xlsx