A multi-omics approach to visualize early neuronal differentiation in 4D

Abstract

SummaryNeuronal differentiation of pluripotent stem cells is an established method to study physiology, disease and medication safety. However, the sequence of events in human neuronal differentiation and the ability of in vitro models to recapitulate early brain development are poorly understood. We developed a protocol optimized for the study of early human brain development and neuropharmacological applications. We comprehensively characterized gene expression and epigenetic profiles at four timepoints, as the cells differentiate from embryonic stem cells towards a heterogenous population of progenitors, immature and mature neurons bearing telencephalic signatures. A multi-omics roadmap of neuronal differentiation, combined with searchable interactive gene analysis tools, allows for extensive exploration of early neuronal development and the effect of medications.Graphical AbstractHighlightsMulti-omics charting a new neuronal differentiation protocol for human ES cellsSingle-cell analyses reveals marker genes during neuronal differentiationIdentified transcriptional waves similar to early human brain developmentSearchable tools to visualize single-cell gene expression and chromatin stateIn BriefWe have developed a novel protocol for human embryonic stem cells to study neural induction and early neuronal differentiation. Multi-omics analyses uncovered cell populations, genes and transcriptional waves defining cell fate commitment. We comprehensively describe epigenetic landscapes and gene expression and provide searchable analysis tools for exploration of the data.