Gene expression and alternative splicing analysis in a large-scale Multiple Sclerosis study.

Autor:	Sak M; Kentucky IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Louisville, Louisville, Kentucky 40202, United States of America.; Department of Neuroscience Training, University of Louisville, Louisville, Kentucky 40202, United States of America., Chariker JH; Kentucky IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Louisville, Louisville, Kentucky 40202, United States of America.; Department of Neuroscience Training, University of Louisville, Louisville, Kentucky 40202, United States of America., Park JW; Kentucky IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Louisville, Louisville, Kentucky 40202, United States of America.; Department of Medicine, University of Louisville, Louisville, Kentucky 40202, United States of America.; Brown Cancer Center Bioinformatics Core, University of Louisville, Louisville, Kentucky 40202, United States of America.; Center for Integrative Environmental Health Sciences Biostatistics and Informatics Facility Core, University of Louisville, Louisville, Kentucky 40202, United States of America., Rouchka EC; Kentucky IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Louisville, Louisville, Kentucky 40202, United States of America.; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky 40202, United States of America.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Aug 16. Date of Electronic Publication: 2024 Aug 16.
DOI:	10.1101/2024.08.16.24312099
Abstrakt:	Background: Multiple Sclerosis (MS) is an autoimmune neurodegenerative disease affecting approximately 3 million people globally. Despite rigorous research on MS, aspects of its development and progression remain unclear. Understanding molecular mechanisms underlying MS is crucial to providing insights into disease pathways, identifying potential biomarkers for early diagnosis, and revealing novel therapeutic targets for improved patient outcomes. Methods: We utilized publicly available RNA-seq data (GSE138614) from post-mortem white matter tissues of five donors without any neurological disorder and ten MS patient donors. This data was interrogated for differential gene expression, alternative splicing and single nucleotide variants as well as for functional enrichments in the resulting datasets. Results: A comparison of non-MS white matter (WM) to MS samples yielded differentially expressed genes involved in adaptive immune response, cell communication, and developmental processes. Genes with expression changes positively correlated with tissue inflammation were enriched in the immune system and receptor interaction pathways. Negatively correlated genes were enriched in neurogenesis, nervous system development, and metabolic pathways. Alternatively spliced transcripts between WM and MS lesions included genes that play roles in neurogenesis, myelination, and oligodendrocyte differentiation, such as brain enriched myelin associated protein ( BCAS1 ), discs large MAGUK scaffold protein 1 ( DLG1 ), KH domain containing RNA binding ( QKI ), and myelin basic protein ( MBP ). Our approach to comparing normal appearing WM (NAWM) and active lesion (AL) from one donor and NAWM and chronic active (CA) tissues from two donors, showed that different IgH and IgK gene subfamilies were differentially expressed. We also identified pathways involved in white matter injury repair and remyelination in these tissues. Differentially spliced genes between these lesions were involved in axon and dendrite structure stability. We also identified exon skipping events and spontaneous single nucleotide polymorphisms in membrane associated ring-CH-type finger 1 ( MARCHF1 ), UDP glycosyltransferase 8 ( UGT8 ), and other genes important in autoimmunity and neurodegeneration. Conclusion: Overall, we identified unique genes, pathways, and novel splicing events affecting disease progression that can be further investigated as potential novel drug targets for MS treatment. Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu