Biology subjects

Kabbe, M.

Publications and source records attributed to Kabbe, M..

8 recordsLinked to original sources

bioRxiv2025

Oligodendroglia as functional effectors of Multiple Sclerosis risk variants

Multiple sclerosis (MS) is a neuroinflammatory disease for which a large number of non-coding single nucleotide polymorphisms (SNPs) have been associated with disease risk/susceptibility. Immune cells have been suggested as the principal functional effector cell types of these common variants. Here, we identify 76 MS-associated SNPs whose loci present accessible chromatin in homeostatic and diseased oligodendroglia (OLG), including both oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (MOLs). By applying high-throughput functional genomics, we found that a subset of these SNPs led to variant- and cell-specific regulatory effects in human induced pluripotent stem cell-derived oligodendroglia. Phenotypic profiling of these variants indicated that rs483180:PHGDH interfered with human OPC proliferation via long-range chromatin interactions with the S100A6 locus, while variants at rs2248137:CYP24A1 impaired oligodendrocyte differentiation by regulating BCAS1 expression. In addition, variants at rs1415069:DIPK1A enhanced secretion of the cytokine CCL2 by oligodendroglia, suggesting that these variants might be implicated in OLG-driven immune cell recruitment in MS. These findings position oligodendroglia as important drivers of MS pathogenesis through modulation of both their cell-intrinsic oligodendroglial function and intercellular communication by non-coding MS risk variants.

cell biology↗

bioRxiv2024

TAF1-dependent transcriptional dysregulation underlies multiple sclerosis

A major conceptual and clinical challenge in multiple sclerosis (MS) is understanding the mechanisms that drive the central nervous system (CNS)-resident neuroinflammation and neurodegeneration underneath disease progression. Genome-wide association studies (GWAS) have implicated RNA polymerase II (RNAPII) promoter-proximal pausing in oligodendrocyte pathology, but the causal mechanisms remain unclear. Here we find that the C-terminal region of TAF1, a core component of the general transcription factor TFIID, is underdetected in progressive MS brains, which can be explained by endoproteolysis due to extralysosomal cathepsin B (CTSB). Mice lacking the C-terminal TAF1 domain (Taf1d38) exhibit MS-like brain transcriptomic signature, alongside CNS-resident inflammation, progressive demyelination, and motor disability. Mechanistically, C-terminal TAF1 interacts with MS-linked factors that cooperate to regulate RNAPII pausing, particularly affecting oligodendroglial myelination genes. These findings uncover a previously unrecognized transcriptional mechanism underlying MS progression and establish a tractable in vivo model for therapeutic development.

neuroscience↗

bioRxiv2024

Single-nuclei histone modification profiling of the adult human central nervous system unveils epigenetic memory of developmental programs

The adult human central nervous system (CNS) is remarkably complex, with neural cells displaying extensive transcriptional heterogeneity. However, how different layers of epigenetic regulation underpin this heterogeneity is poorly understood. Here, we profile the adult human CNS from distinct regions, for chromatin accessibility at the single-nuclei level. In addition, we simultaneously co-profiled the histone modifications H3K27me3 and H3K27ac at the single nuclei-level, providing their first map in all major human CNS cell types. We unveil primed chromatin signatures at HOX loci in spinal cord-derived human oligodendroglia (OLG) but not microglia. These signatures were reminiscent of developmental OLG but were decoupled from robust gene expression. Moreover, using high-resolution Micro-C, we show that induced pluripotent stem cell (iPS) derived human OLGs exhibit a HOX chromatin architecture compatible with the primed chromatin in adult OLGs, and bears a strong resemblance not only to OLG developmental architecture, but also high-grade pontine gliomas. Thus, adult OLG retain epigenetic memory from developmental states, which might enable them to promptly transcribe Hox genes, in contexts of regeneration, but also make them susceptible to gliomagenesis.

neuroscience↗

bioRxiv2023

Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease that targets mature oligodendrocytes (MOLs) and their myelin. MOLs are transcriptionally heterogeneous and can transition to immune-like states in the context of MS. However, the intricacies of their dynamics throughout disease progression remain poorly understood. Here, we employed simultaneous single-cell multiome ATAC and RNA sequencing targeting oligodendroglia (OLGs) from the experimental autoimmune encephalomyelitis (EAE) MS mouse model at different stages of the disease course. We found that the transition to immune OLG states appear already at the early stages of EAE and persist to the late stages of the disease. Interestingly, transcription factor activity suggested immunosuppression in MOLs at early stages of EAE and we also observed a transitory activation of a regenerative program in MOLs at this stage. Importantly, different MOLs exhibit a differential responsiveness to EAE, with MOL2 exhibiting a stronger transcriptional immune response than MOL5/6. Moreover, we observed divergent responses at the epigenetic level of MOL2 and MOL5/6 during disease evolution. Thus, our single-cell multiomic resource highlights dynamic and distinct responses of OLG subpopulations to the evolving environment in EAE, which might modulate their response to regenerative therapeutic interventions in MS.

neuroscience↗

bioRxiv2022

Marked regional glial heterogeneity in the human white matter of the central nervous system

The myelinated white matter tracts of the central nervous system (CNS) are essential for fast transmission of electrical impulses and are commonly affected in neurodegenerative diseases. However, these often uniquely human diseases differentially affect white matter regions, at various ages and between males and females, and we hypothesised that this is secondary to physiological variation in white matter glia with region, age and sex. Using single nucleus RNA sequencing of healthy human post-mortem samples, we find marked glial heterogeneity with tissue region (primary motor cortex, cerebellum, cervical spinal cord), with tissue-specific cell populations of oligodendrocyte precursor cells and astrocytes, and a spinal cord-enriched oligodendrocyte type that appears human-specific. Spinal cord microglia but not astrocytes show a more activated phenotype compared to brain. These regional effects, with additional differentially expressed genes with age and sex in all glial lineages, help explain pathological patterns of disease - essential knowledge for therapeutic strategies.

neuroscience↗

bioRxiv2021

Developmental landscape of human forebrain at a single-cell level unveils early waves of oligodendrogenesis

Oligodendrogenesis in the human central nervous system has been mainly observed at the second trimester of gestation, a much later developmental stage compared to mouse. Here we characterize the transcriptomic neural diversity in the human forebrain at post conceptual weeks (PCW) 8 to 10, using single-cell RNA-Seq. We find evidence of the emergence of a first wave of oligodendrocyte lineage cells as early as PCW 8, which we also confirm at the epigenomic level with single-cell ATAC-Seq. Using regulatory network inference, we predict key transcriptional events leading to the specification of oligodendrocyte precursor cells (OPCs). Moreover, by profiling the spatial expression of fifty key genes using In Situ Sequencing (ISS), we identify regions in the human ventral fetal forebrain where oligodendrogenesis first occurs. Our results indicate evolutionary conservation of the first wave of oligodendrogenesis between mouse and human and describe regulatory mechanisms required for human OPC specification.

neuroscience↗

bioRxiv2020

Single-cell profiling of histone modifications in the mouse brain

The development of the mouse central nervous system (CNS) involves coordinated execution of transcriptional and epigenetic programs. These programs have been extensively studied through single-cell technologies in a pursuit to characterize the underlying cell heterogeneity. However, histone modifications pose additional layers of both positive and negative regulation that defines cellular identity. Here we show that the Cut&Tag technology can be coupled with a droplet-based single cell library preparation platform to produce high quality chromatin modifications data at a single cell resolution in tens of thousands of cells. We apply single-cell Cut&Tag (scC&T) to probe histone modifications characteristic of active promoters (H3K4me3), active promoters and enhancers (H3K27ac), active gene bodies (H3K36me3) and inactive regions (H3K27me3) and generate scC&T profiles for almost 50,000 cells. scC&T profiles of each of these histone modifications were sufficient to determine cell identity and deconvolute at single cell level regulatory principles such as promoter bivalency, spreading of H3K4me3 and promoter-enhancer connectivity. Moreover, we used scC&T to investigate the single-cell chromatin occupancy of transcription factor Olig2 and the cohesin complex component Rad21. Our results indicate that analysis of histone modifications and transcription factor occupancy at a single cell resolution can provide unique insights of epigenomic landscapes in the CNS. We also provide an online resource that can be used to interactively explore the data at https://castelobranco.shinyapps.io/BrainCutAndTag2020/.

neuroscience↗

bioRxiv2020

A primed immune transcriptional program is activated in oligodendroglia in multiple sclerosis

Multiple sclerosis (MS) is a disease characterized by a targeted immune attack on myelin in the central nervous system (CNS). We have previously shown that oligodendrocytes (OLs), myelin producing cells in the CNS, and their precursors (OPCs), ac-quire disease-specific transcriptional states in MS 1,2. To under-stand how these alternative transcriptional programs are acti-vated in disease, we performed single-cell assay for transposase accessible chromatin using sequencing (scATAC-seq) on the OL lineage in the experimental autoimmune encephalomyeli-tis (EAE) mouse model of MS. We identified regulatory regions with increased accessibility in oligodendroglia (OLG) in EAE, some of which in the proximity of immune genes. A similar re-modeling of chromatin accessibility was observed upon treat-ment of postnatal OPCs with interferon-gamma (IFN{gamma}), but not with dexamethasone. These changes in accessibility were not exclusive to distal enhancers, but also occurred at promoter re-gions, suggesting a role for promoters in mediating cell-state transitions. Notably, we found that a subset of immune genes al-ready exhibited chromatin accessibility in OPCs ex vivo and in vivo, suggesting a primed chromatin state in OLG compatible with rapid transitions to an immune-competent state. Several primed genes presented bivalency of H3K4me3 and H3K27me3 at promoters in OPCs, with loss of H3K27me3 upon IFN{gamma} treatment. Inhibition of JMJD3/Kdm6b, mediating removal of H3K27me3, led to the inability to activate these genes upon IFN{gamma} treatment. Importantly, OLGs from the adult human brain showed chromatin accessibility at immune gene loci, par-ticularly at MHC-I pathway genes. A subset of single-nucleotide polymorphisms (SNPs) associated with MS susceptibility over-lapped with these primed regulatory regions in OLG from both mouse and human CNS. Our data suggest that susceptibility for MS may involve activation of immune gene programs in OLG. These programs are under tight control at the chromatin level in OLG and may therefore constitute novel targets for immunological-based therapies for MS.

neuroscience↗