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Early shaping of the chromatin landscape specifies vagal neural crest into distinct lineages [RNA-seq]

ABSTRACT: Complex traits in enteropathies like Hirschsprung disease underscores a larger gene regulatory network (GRN) driving vagal neural crest (VNC) to form the enteric nervous system (ENS). To dissect the GRN and understand the function of non-coding regulatory regions, we used a novel highly conserved EdnrB E2 enhancer with a FoxD3 NC2 enhancer to generate a comprehensive map of VNC chromatin and transcriptional landscape during ENS development. Together with single-cell transcriptional profiles, we revealed three distinct lineages of VNC (glial, neuronal, and mesenchymal) that are each pre-specified by independent GRNs before delamination. We identified and functionally validated regulatory cores mediating the glial (Tfap2B and Sox10) and neuronal programmes (Sox3/Msx1) that in spatiotemporal combinations with other families of transcription factors, control the timing of enteric cell differentiation. Deconstructing the VNC-GRN identifies factors that pre-specifies cells to their presumptive fate and sheds light on how early GRN dysregulations influence the divergent neural phenotype in enteropathies.

ORGANISM(S): Gallus gallus

PROVIDER: GSE125709 | GEO | 2019/11/27

REPOSITORIES: GEO

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Early chromatin shaping predetermines multipotent vagal neural crest into neural, neuronal and mesenchymal lineages

Project description:The enteric nervous system (ENS) predominantly originates from vagal neural crest cells (VNC) that emerge from the caudal hindbrain, invade the foregut and populate the gastrointestinal tract. However, the gene regulatory network (GRN) orchestrating the early specification of VNC remains unknown. Using an EdnrB enhancer, we generated a comprehensive temporal map of the chromatin and transcriptional landscape of VNC in the avian model, revealing three VNC cell clusters (neural, neurogenic and mesenchymal), each predetermined epigenetically prior to neural tube delamination. We identify and functionally validate regulatory cores (Sox10/Tfap2B/SoxB/Hbox) mediating each programme and elucidate their combinatorial activities with other spatiotemporally-specific transcription factors (bHLH/NR). Our global deconstruction of the VNC-GRN in vivo sheds light on critical early regulatory mechanisms that may influence the divergent neural phenotypes in enteric neuropathies.

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Project description:The receptor tyrosine kinase gene RET plays a critical role in the fate specification of enteric neural crest cells (ENCCs) during enteric nervous system (ENS) development. Pathogenic RET loss of function (LoF) alleles are associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. ENCCs invade the developing GI tract, proliferate, migrate caudally, and differentiate into all of the major ENS cell types. Although the major phenotypic consequences, and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, its cell type and state-specific effects are unknown. Consequently, we performed single-cell RNA sequencing (scRNA-seq) on an enriched population of ENCCs isolated from the developing GI tract of Ret null heterozygous and homozygous mouse embryos at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: (1) Ret-expressing ENCCs are a heterogeneous population composed of ENS progenitors as well as glial and neuronal committed cells; (2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; (3) HSCR-associated and Ret gene regulatory network genes exhibit distinct expression patterns across Ret-expressing ENCC cells with their expression impacted by Ret LoF; and (4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes and that Ret LoF contributes to GI aganglionosis in multiple independent ways.

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