A5088625820- Pluripotent Stem Cells Research
- Single-cell and spatial transcriptomics
- Neuroscience and Neuropharmacology Research
- Neuroscience and Neural Engineering
- Genetics and Neurodevelopmental Disorders
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Chromatin Remodeling and Cancer
- CRISPR and Genetic Engineering
- Cellular Mechanics and Interactions
- Child and Animal Learning Development
- Advanced biosensing and bioanalysis techniques
- Ion channel regulation and function
- Neural dynamics and brain function
- Hippo pathway signaling and YAP/TAZ
- Gene Regulatory Network Analysis
ETH Zurich
2021-2024
Radboud University Nijmegen
2018-2021
Radboud University Medical Center
2018-2021
Self-organizing neural organoids grown from pluripotent stem cells
Abstract Induced pluripotent stem cell (iPSC)-derived organoids provide models to study human organ development. Single-cell transcriptomics enable highly resolved descriptions of states within these systems; however, approaches are needed directly measure lineage relationships. Here we establish iTracer, a recorder that combines reporter barcodes with inducible CRISPR–Cas9 scarring and is compatible single-cell spatial transcriptomics. We apply iTracer explore clonality dynamics during...
Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic GABAergic neurons. A growing number studies imply that disruption this E/I balance is commonality many disorders; however, obtaining mechanistic insight into these disruptions, with translational value for patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) associated autism...
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...
Pathogenic mutations in either one of the epigenetic modifiers EHMT1, MBD5, MLL3, or SMARCB1 have been identified to be causative for Kleefstra syndrome spectrum (KSS), a neurodevelopmental disorder with clinical features both intellectual disability (ID) and autism (ASD). To understand how these variants lead phenotypic convergence KSS, we employ loss-of-function approach assess neuronal network development at molecular, single-cell, activity level. KSS-gene-deficient networks all develop...
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,...
Abstract Brain organoids enable the mechanistic study of human brain development, and provide opportunities to explore self-organization in unconstrained developmental systems. Here, we establish long-term, live light sheet microscopy on unguided generated from fluorescently labeled induced pluripotent stem cells, which enables tracking tissue morphology, cell behaviors, subcellular features over weeks organoid development. We a novel dual-channel, multi-mosaic multi-protein labeling...
Summary Activity in the healthy brain relies on concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic GABAergic neurons. A growing number studies imply that disruption this E/I balance is a commonality many disorders, however, obtaining mechanistic insight into these disruptions, with translational value for human patient, has typically been hampered by methodological limitations. Cadherin-13 ( CDH13 ) strongly associated to...
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...
Abstract An intriguing question in medical biology is how mutations functionally distinct genes can lead to similar clinical phenotypes. For example, patients with epigenetic regulators EHMT1, MBD5, MLL3 or SMARCB1 share the core features of intellectual disability (ID), autism spectrum disorder (ASD) and facial dysmorphisms. To elucidate these phenotypic similarities are reflected by convergence at molecular, cellular neuronal network level, we directly compared effects their loss function...