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From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions [methylation]

ABSTRACT: We compared genome-wide DNA methylation profiles between chronically demyelinated MS lesions and matched normal-appearing white matter (NAWM).

ORGANISM(S): Homo sapiens

PROVIDER: GSE224455 | GEO | 2023/06/29

REPOSITORIES: GEO

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From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions [RNA-seq]

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Project description:Using laser capture microscopy, white (WM) and grey matter (GM) demyelinated areas and normal appearing matter was collected from histologically verified leukocortical lesions from snap-frozen human post mortem tissuederived from Multiple Sclerosis patients. Our data shows large differences in gene expression in WM and GM demyelinated areas (compared to their respective normal appearing matter) even when the demyelinated areas are spatially connected such as in leukocortical lesions. Thus, we show that WM demyelinated areas and GM demyelinated areas are distinct entities with distinct pathology. Therefore findings observed in WM demyelinated areas cannot be generalized to GM demyelinated areas.

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Project description:Age-associated deep-subcortical white matter lesions (DSCL) are an independent risk factor for dementia, displaying high levels of CD68+ microglia. This study aimed to characterise the transcriptomic profile of microglia in DSCL and surrounding radiologically normal-appearing white matter (NAWM) compared to non-lesional control white matter. CD68+ microglia were isolated from white matter groups (n=4 cases per group) from the Cognitive Function and Ageing Study neuropathology cohort by immuno-laser capture microdissection. Microarray gene expression profiling, but not RNA-sequencing, was found to be compatible with immuno-LCM-ed post-mortem material and identified significantly differentially expressed genes (DEG). Functional grouping and pathway analysis was assessed using DAVID, and immunohistochemistry was performed to validate gene expression changes at the protein level. Transcriptomic profiling of microglia in DSCL compared to non-lesional control white matter identified 181 significant DEG (93 upregulated and 88 downregulated). Functional clustering analysis revealed dysregulation of haptoglobin-hemoglobin binding (Enrichment score 2.15, p=0.017), confirmed by CD163 immunostaining, suggesting a neuroprotective microglial response to blood-brain barrier dysfunction in DSCL. In NAWM versus control white matter, microglia exhibited 347 DEGs (209 upregulated, 138 downregulated), with significant dysregulation of protein de-ubiquitination (Enrichment score 5.14, p<0.0001), implying an inability to maintain protein homeostasis in NAWM that may contribute to lesion spread. These findings enhance understanding of microglial transcriptomic changes in aging white matter pathology, highlighting a neuroprotective adaptation in DSCL microglia and a potentially lesion-promoting phenotype in NAWM microglia.

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Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role

Project description:Gene expression profiling has been performed on astrocytes isolated using laser capture microdissection (LCM) from multiple sclerosis normal appearing white matter (NAWM) and control WM to identify whether specific glial changes exist in NAWM which contribute to lesion development or prevent disease progression

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Oxidative damage and respiratory burst in Multiple Sclerosis

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From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-06-29 | GSE224457 | GEO

Gene expression of white and grey matter demyelinated areas and normal appearing matter from Multiple Sclerosis leukocortial lesions of human post-mortem tissue

Project description:Gene expression of white and grey matter demyelinated areas and normal appearing matter from Multiple Sclerosis leukocortial lesions of human post-mortem tissue

| PRJNA627961 | ENA

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