A5086405035- Single-cell and spatial transcriptomics
- Pluripotent Stem Cells Research
- Gene Regulatory Network Analysis
- RNA Research and Splicing
- Cell Image Analysis Techniques
- Gut microbiota and health
- Genomics and Chromatin Dynamics
- Colorectal Cancer Screening and Detection
- Gene expression and cancer classification
- CRISPR and Genetic Engineering
- Protist diversity and phylogeny
- Neurogenesis and neuroplasticity mechanisms
- Heat shock proteins research
- Epigenetics and DNA Methylation
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA modifications and cancer
- Retinal Development and Disorders
- Cancer Cells and Metastasis
- Biomedical Ethics and Regulation
- Endoplasmic Reticulum Stress and Disease
- 3D Printing in Biomedical Research
- Genomics and Phylogenetic Studies
- Helicobacter pylori-related gastroenterology studies
- Cancer Genomics and Diagnostics
- Machine Learning in Bioinformatics
ETH Zurich
2019-2024
Roche (Switzerland)
2023-2024
Science for Life Laboratory
2021-2023
Karolinska University Hospital
2021-2023
Karolinska Institutet
2021-2023
European Molecular Biology Laboratory
2019
Self-organizing neural organoids grown from pluripotent stem cells
Abstract The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders 1–4 . Cerebral organoids enable study a context. We have developed CRISPR–human organoids–single-cell RNA sequencing (CHOOSE) system, which uses verified pairs guide RNAs, inducible CRISPR–Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening mosaic organoids. Here we show perturbation 36...
Salamanders are tetrapod models to study brain organization and regeneration; however, the identity evolutionary conservation of cell types largely unknown. We delineated populations in axolotl telencephalon during homeostasis regeneration using single-cell genomic profiling. identified glutamatergic neurons with similarities amniote hippocampus, dorsal lateral cortex, conserved γ-aminobutyric acid-releasing (GABAergic) neuron classes. inferred transcriptional dynamics gene regulatory...
Abstract Organoids generated from human pluripotent stem cells provide experimental systems to study development and disease, but quantitative measurements across different spatial scales molecular modalities are lacking. In this study, we multiplexed protein maps over a retinal organoid time course primary adult tissue. We developed toolkit visualize progenitor neuron location, the arrangements of extracellular subcellular components global patterning in each addition, single-cell...
Human neural organoids, generated from pluripotent stem cells in vitro, are useful tools to study human brain development, evolution and disease. However, it is unclear which parts of the covered by existing protocols, has been difficult quantitatively assess organoid variation fidelity. Here we integrate 36 single-cell transcriptomic datasets spanning 26 protocols into one integrated cell atlas totalling more than 1.7 million cells1–26. Mapping developing references27–30 shows primary types...
Abstract Cell fate progression of pluripotent progenitors is strictly regulated, resulting in high human cell diversity. Epigenetic modifications also orchestrate restriction. Unveiling the epigenetic mechanisms underlying diversity has been difficult. In this study, we use brain and retina organoid models present single-cell profiling H3K27ac, H3K27me3 H3K4me3 histone from progenitor to differentiated neural fates reconstruct epigenomic trajectories regulating identity acquisition. We...
Biosynthetic gene clusters (BGCs) are enticing targets for (meta)genomic mining efforts, as they may encode novel, specialized metabolites with potential uses in medicine and biotechnology. Here, we describe GECCO (GEne Cluster prediction COnditional random fields; https://gecco.embl.de ), a high-precision, scalable method identifying novel BGCs data using conditional fields (CRFs). Based on an extensive evaluation of de novo BGC prediction, found to be more accurate over 3x faster than...
A next step for cell atlases should be to chart perturbations in human model systems.
Self-organizing cerebral organoids grown from pluripotent stem cells combined with single-cell genomic technologies provide opportunities to explore gene regulatory networks (GRNs) underlying human brain development. Here we acquire transcriptome and accessible chromatin profiling data over a dense time course covering multiple phases of organoid development including neuroepithelial formation, patterning, regionalization, neurogenesis. We identify temporally dynamic region-specific regions,...
Neural tissues generated from human pluripotent stem cells in vitro (known as neural organoids) are becoming useful tools to study brain development, evolution and disease. The characterization of organoids using single-cell genomic methods has revealed a large diversity cell types with molecular signatures similar those observed primary tissue. However, it is unclear which domains the nervous system covered by existing protocols. It also difficult quantitatively assess variation between...
Morphogens, secreted signalling molecules that direct cell fate and tissue development, are used to neuroepithelial progenitors towards discrete regional identities across the central nervous system. Neural tissues derived from pluripotent stem cells in vitro (neural organoids) provide new models for studying neural regionalization, however, we lack a comprehensive survey of how developing human neuroepithelium responds morphogen cues. Here, produce detailed map morphogen-induced effects on...
G3BP is the central node within stress-induced protein–RNA interaction networks known as stress granules (SGs). The SG-associated proteins Caprin-1 and USP10 bind mutually exclusively to NTF2 domain of G3BP1, promoting inhibiting SG formation, respectively. Herein, we present crystal structure G3BP1-NTF2 in complex with a Caprin-1-derived short linear motif (SLiM). interacts His-31 His-62 third NTF2-binding site outside those covered by USP10, confirmed using biochemical biophysical-binding...
Development of the human brain involves processes that are not seen in many other species, but can contribute to neurodevelopmental disorders (1–4). Cerebral organoids be used investigate a context limited by variability and low throughput. We have developed CRISPR-human organoids-scRNA-seq (CHOOSE) system utilizes verified pairs gRNAs, inducible CRISPR/Cas9-based genetic disruption, single-cell transcriptomics for pooled loss-of-function screening mosaic organoids. Genetic perturbations 36...
Organoids generated from human pluripotent stem cells (PSCs) provide experimental systems to study development and disease. However, we lack quantitative spatiotemporal descriptions of organoid that incorporate measurements across different molecular modalities. Here focus on the retina use a single-cell multimodal approach reconstruct retinal development. We establish an computational pipeline generate multiplexed spatial protein maps over time course primary adult retina, registering...
Human stem cells can generate complex, multicellular epithelial tissues of endodermal origin in vitro that recapitulate aspects developing and adult human physiology. These tissues, also called organoids, be derived from pluripotent or tissue-resident fetal cells. However, it has remained difficult to understand the precision accuracy organoid cell states through comparison with primary counterparts, comprehensively assess similarity differences between protocols. Advances computational...
ABSTRACT The human brain has changed dramatically since humans diverged from our closest living relatives, chimpanzees and the other great apes 1–5 . However, genetic developmental programs underlying this divergence are not fully understood 6–8 Here, we have analyzed stem cell-derived cerebral organoids using single-cell transcriptomics (scRNA-seq) accessible chromatin profiling (scATAC-seq) to explore gene regulatory changes that specific humans. We first analyze cell composition...
ABSTRACT Self-organizing tissues resembling brain regions grown in vitro from human stem cells (so-called organoids or spheroids) offer exciting possibilities to study development, disease, and evolution. Brain spheroids are complex can contain at various stages of differentiation different structures. Single-cell genomic methods provide powerful approaches explore cell composition, trajectories, gene regulation, genetic perturbations organoid systems. However, it remains a major challenge...
Salamanders are important tetrapod models to study brain organization and regeneration, however the identity evolutionary conservation of cell types is largely unknown. Here, we delineate populations in axolotl telencephalon during homeostasis representing first single-cell genomic spatial profiling an anamniote brain. We identify glutamatergic neurons with similarities amniote hippocampus, dorsal lateral cortex, conserved GABAergic neuron classes. infer transcriptional dynamics gene...
Abstract G3BP is the central hub within protein-RNA interaction network of stress-induced bio-molecular condensates known as stress granules (SG). The SG-associated proteins Caprin-1 and USP10 exhibit mutually exclusive binding to structured NTF2-domain G3BP1, thereby regulating G3BP1-mediated condensation, but with opposite effects: promotes inhibits SG formation. Herein, we present crystal structure G3BP1-NTF2 in complex a derived short linear motif (SLiM), which provides molecular...
Abstract Human cell type diversity emerges through a highly regulated series of fate restrictions from pluripotent progenitors. Fate restriction is orchestrated in part epigenetic modifications at genes and regulatory elements, however it has been difficult to study these mechanisms humans. Here, we use organoid models the human central nervous system establish single-cell profiling histone (H3K27ac, H3K27me3, H3K4me3) cells over time course reconstruct epigenomic trajectories governing...