From Pioneer to Repressor: Bimodal foxd3 Activity Dynamically Remodels Neural Crest Regulatory Landscape In Vivo

Summary

The neural crest (NC) is a transient embryonic stem cell-like population characterized by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3-mutant cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3-expressing premigratory NC, our analysis shows that, during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, foxd3 then gradually switches from an activator to its well-described role as a transcriptional repressor and potentially uses differential partners for each role. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from “permissive” to “repressive” nucleosome and chromatin organization to maintain multipotency and define cell fates.

Graphical Abstract

Highlights

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  FoxD3 primes neural crest specification by modulating distal enhancers

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  FoxD3 represses a number of neural crest migration and differentiation genes

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  In neural crest, FoxD3 acts to switch chromatin from “permissive” to “repressive”

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  Distinctive gene regulatory mechanisms underlie the bimodal action of FoxD3

Abstract

Through transcriptional and epigenomic profiling of foxd3-mutant zebrafish neural crest cells (NCCs) and whole-genome mapping of FoxD3 binding, Lukoseviciute et al. uncover bimodal FoxD3 action across NCC development. FoxD3 acts as a pioneer factor to prime genes for NCC specification before switching to being a repressor to control migration and differentiation.