Single-cell RNA-seq has revealed cellular heterogeneity in the developing mammalian cerebellum, yet the regulatory logic underlying the cellar diversity remains unclear. Using integrated single-cell RNA and ATAC analyses of embryonic mouse cerebella, we resolved developmental trajectories of cerebellar progenitors and identified putative trans- and cis-elements that control cell state transition. We reverse-engineered gene regulatory networks (GRNs) of each cell type or state. Via in silico simulations and in vivo experiments, we validated the efficacy of GRN analyses and uncovered the molecular control of a newly identified stem zone, the posterior transitory zone (PTZ), which contains multipotent progenitors for Bergmann glia, granule neurons, and choroid plexus epithelium. Importantly, we showed that perturbing cell fate specification of PTZ progenitors results in posterior cerebellar vermis hypoplasia, the most common cerebellar birth defect in humans. Our results provide a foundation for comprehensive studies of developmental programs of the mammalian cerebellum.
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E10.5-E17.5 (Carter et al) ; E10.5-E13.5 (Carter et al) ; E12.5 (in-house) ;
Putative CREs across cell types can be inspected as custom UCSC genome browser tracks at: https://genome.ucsc.edu/cgi-bin/hgTracks?db=mm10&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr19%3A44639167%2D44771728&hgsid=1137604013_RLLejstQcaKqkkIkFKB7ItyAr7ub.
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Integrated single-cell transcriptomic and epigenetic analyses of cell-state transition and lineage commitment in the embryonic mouse cerebellum
Nagham Khouri-Farah†, Qiuxia Guo†, Kerry Morgan, Jihye Shin, and James Y.H. Li (2021)