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- Single-Cell and Spatial Transcriptomics and Epigenomics of Oligodendroglia in Development and in Multiple Sclerosis
Single-Cell and Spatial Transcriptomics and Epigenomics of Oligodendroglia in Development and in Multiple Sclerosis
Centre de recherche - Paris
Amphithéâtre Marie Curie
Pavillon Curie, 11 rue Pierre & Marie Curie, Paris 5ème
Description
Oligodendroglia (OLG) mediate myelination of neurons, a process that allows efficient electrical impulse transmission in the central nervous system. An autoimmune response in multiple sclerosis (MS) leads to OLG cell death, loss of myelin and neuropathology. Using single cell transcriptomics, we have previously identified disease-specific OLG populations in the EAE mouse model of MS and in human MS brain archival tissue, characterized by the expression of immune genes.Â
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By assessing chromatin accessibility and the transcriptome simultaneously at the single cell level at different stages of the disease course, we found that immune genes exhibit a primed chromatin state in mouse and human OLG in a non-disease context, compatible with rapid transitions to immune-competent states in MS. Moreover, we found dynamic and distinct transcriptomic and epigenomic responses of OLG subpopulations to the evolving environment in EAE mouse model of MS, which might modulate their response to regenerative therapeutic interventions in MS.
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While single-cell genomics are powerful for investigating disease-specific cellular states, these methods involve isolating the tissue under study from its niche, leading to a loss of spatial information. Such information is essential for determining cell-to-cell communication in disease niches. We have applied in situ sequencing to investigate disease evolution in MS at a spatial level, both in the EAE mouse model of MS and in human post-mortem MS samples. We annotated disease neighborhoods during lesion evolution and found centrifugal propagation of active lesions. We demonstrated that disease-associated (DA)-glia arise independently of lesions and are dynamically induced and resolved over the disease course.
We have also applied dBIT-Seq, a ligation-based method for deterministic barcoding in tissue, to probe different histone modifications and chromatin accessibility in the mouse brain tissue sections, either in an unimodal or simultaneously with transcriptomics. This spatial epigenome–transcriptome co-profiling has allowed us to identify cellular lineage progression and epigenomic priming events that precede transcription during development with spatial resolution. We are currently applying these methods to disease paradigms in MS, to uncover how transitions to pathological cellular states occur at epigenomic and transcriptomic levels.
Organisateurs
Scientific Project Manager Iro Triantafyllakou
Orateurs
Gonçalo Castelo-Branco
Department of Medical Biochemistry and Biophysics at Karolinska Institute, Sweden
Invité(es) par
Celine Vallot
Institut Curie