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Abstract
BackgroundInvestigating cell fate decision and subpopulation specification in the context of the neural lineage is fundamental to understanding neurogenesis and neurodegenerative diseases. The differentiation process of neural-tube-like rosettes in vitro is representative of neural tube structures, which are composed of radially organized, columnar epithelial cells and give rise to functional neural cells. However, the underlying regulatory network of cell fate commitment during early neural differentiation remains elusive.ResultsIn this study, we investigated the genome-wide transcriptome profile of single cells from six consecutive reprogramming and neural differentiation time points and identified cellular subpopulations present at each differentiation stage. Based on the inferred reconstructed trajectory and the characteristics of subpopulations contributing the most toward commitment to the central nervous system lineage at each stage during differentiation, we identified putative novel transcription factors in regulating neural differentiation. In addition, we dissected the dynamics of chromatin accessibility at the neural differentiation stages and revealed active cis-regulatory elements for transcription factors known to have a key role in neural differentiation as well as for those that we suggest are also involved. Further, communication network analysis demonstrated that cellular interactions most frequently occurred in the embryoid body stage and that each cell subpopulation possessed a distinctive spectrum of ligands and receptors associated with neural differentiation that could reflect the identity of each subpopulation.ConclusionsOur study provides a comprehensive and integrative study of the transcriptomics and epigenetics of human early neural differentiation, which paves the way for a deeper understanding of the regulatory mechanisms driving the differentiation of the neural lineage.
Highlights
Investigating cell fate decision and subpopulation specification in the context of the neural lineage is fundamental to understanding neurogenesis and neurodegenerative diseases
2 Single-cell transcriptome dynamics in human neural differentiation addition, we dissected the dynamics of chromatin accessibility at the neural differentiation stages and revealed active cis-regulatory elements for transcription factors known to have a key role in neural differentiation as well as for those that we suggest are involved
The results showed that many neural transcription factor (TF), such as markers of neural tube formation (SOX4 and SOX11); the neural stem cells (NSCs) self-renewal and proliferation regulator FOXO3; and the NSCs markers NES, CDH2, and FABP7, were commonly expressed across all three branches, indicating the capacity for neural tube development and NSCs proliferation are a fundamental feature of neural rosettes (Additional file 9: Supplementary Fig. S9a, S9b)
Summary
The nervous system contains complex molecular circuitry in developmental processes. In humans, there is a paucity of data describing early neural development and the corresponding cellular heterogeneity at various stages. The differentiation system of human induced pluripotent stem cells (hiPSCs) provides access to the very early stage of neural development and may serve as a source of specialized cells for regenerative medicine as well as support for further investigations of neural tube defects. Bulk ATAC-seq with two biological replicates was applied to the cell stages iPSCs, EB, Ros-E, Ros-L, and NPCs to measure the regulome dynamics during neural differentiation (Fig. 1a). We followed a well-adopted neural induction protocol and generated NPCs by forming neural rosettes via inhibition of transforming growth factors β (TGFβ), AMP-activated protein kinase, and BMP signaling pathways and activation of the FGF signaling pathway [8, 16].
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