Biology subjects

van Bruggen, D.

Publications and source records attributed to van Bruggen, D..

5 recordsLinked to original sources

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↗

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↗

bioRxiv2019

Specific oligodendrocyte populations have differential spatial distribution and susceptibility to injury

Oligodendrocytes (OLs), the myelinating cells of the central nervous system, are transcriptionally heterogeneous,1 the origin and functional consequences of which are unknown. Functional heterogeneity of MOLs might correlate with the local environment or their interactions with different neuron types.2 Here, we show that distinct MOL populations have spatial preference in the mammalian central nervous system and differential susceptibility to traumatic spinal cord injury. We also show that the generation of distinct MOL populations is independent of the OPC developmental origin. We found that OPCs originating from the previously described developmental waves3-5 have comparable potential to differentiate into the main MOL populations. Furthermore, we found that MOL type 2 (MOL2) is enriched in the spinal cord and almost absent in the brain, while MOL5/6 is enriched with age in all analyzed regions. MOL2 and MOL5/6 also have differential preference for motor and sensory tracts in the spinal cord. In the context of disease, we found that MOL2 and MOL5/6 have differential susceptibility to traumatic spinal cord injury, where MOL2 are lost and MOL5/6 increased their contribution to the OL lineage. Importantly, MOL2 susceptibility is disease specific, as we found MOL2 is not lost in a mouse model of multiple sclerosis. Our results demonstrate that the MOL populations, previously described by single-cell transcriptomics,1 have distinct spatial preference and responses. We anticipate our study to pave the way for a better understanding of the MOL populations-specific functional roles in development, health, and disease, allowing for better targeting of the OL subtypes important for the regeneration and repair of the central nervous system.

neuroscience↗

bioRxiv2017

RNA velocity in single cells

RNA abundance is a powerful indicator of the state of individual cells, but does not directly reveal dynamic processes such as cellular differentiation. Here we show that RNA velocity--the time derivative of RNA abundance--can be estimated by distinguishing unspliced and spliced mRNAs in standard single-cell RNA sequencing protocols. We show that RNA velocity is a vector that predicts the future state of individual cells on a timescale of hours. We validate the accuracy of RNA velocity in the neural crest lineage, demonstrate its use on multiple technical platforms, reconstruct the branching lineage tree of the mouse hippocampus, and measure RNA kinetics in human embryonic brain. We expect RNA velocity to greatly aid the analysis of developmental lineages and cellular dynamics, particularly in humans.

genomics↗

bioRxiv2017

Single-cell transcriptomic profiling of progenitors of the oligodendrocyte lineage reveals transcriptional convergence during development

Pdgfra+ oligodendrocyte precursor cells (OPCs) arise in distinct specification waves during embryogenesis in the central nervous system (CNS). It is unclear whether there is a correlation between these waves and different transcriptional oligodendrocyte (OL) states at adult stages. Here we present a bulk and single-cell transcriptomics resource providing insights on how transitions between these states occur. We show that E13.5 Pdgfra+ populations are not OPCs, exhibiting instead hallmarks of neural progenitors. A subset of these progenitors, which we refer as pre-OPCs, rewires their transcriptional landscape, converging into indistinguishable OPC states at E17.5 and post-natal stages. P7 brain and spinal cord OPCs present similar transcriptional profiles at the single-cell level, indicating that OPC states are not region-specific. Postnatal OPC progeny of E13.5 Pdgfra+ have electrophysiological and transcriptional profiles similar to OPCs derived from subsequent specification waves. In addition, lineage tracing indicates that a subset of E13.5 Pdgfra+ cells also originate cells of the pericyte lineage. In summary, our results indicate that embryonic Pdgfra+ cells are diverse and give rise at post-natal stages to distinct cell lineages, including OPCs with convergent transcriptional profiles in different CNS regions.

neuroscience↗